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  • 1.
    Abrahamsson, Annelie
    et al.
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Vazquez Rodriguez, Gabriela
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Dabrosin, Charlotta
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Fulvestrant-Mediated Attenuation of the Innate Immune Response Decreases ER+ Breast Cancer Growth In Vivo More Effectively than Tamoxifen2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 20, p. 4487-4499Article in journal (Refereed)
    Abstract [en]

    Although blocking estrogen-dependent signaling is a cornerstone of adjuvant treatment for breast cancer, 25% of patients experience recurrent disease. Stroma events including innate immune responses are key in cancer progression. How different estrogen receptor (ER)-targeting therapies, including the partial agonist tamoxifen and the pure antagonist fulvestrant, affect the tumor stroma has not yet been elucidated. Fulvestrant is used in only postmenopausal patients, and its effects in the presence of estradiol remain undetermined. Here we observe that fulvestrant decreases ER+ breast cancer growth compared with tamoxifen in the presence of physiologic levels of estradiol in human breast cancer in nude mice and in murine breast cancer in immune-competent mice. Fulvestrant significantly inhibited macrophage and neutrophil infiltration in both models. These effects were corroborated in a zebrafish model where fulvestrant inhibited neutrophil- and macrophage-dependent cancer cell dissemination more effectively than tamoxifen. A comprehensive analysis of 234 human proteins released into the cancer microenvironment by the cancer cells sampled via microdialysis in vivo revealed that 38 proteins were altered following both treatments; 25 of these proteins were associated with immune response and were altered by fulvestrant only. Compared with tamoxifen, fulvestrant significantly affected inflammatory proteins released by murine stroma cells. Importantly, in vivo microdialysis of human ER+ breast cancer revealed that the majority of affected proteins in murine models were upregulated in patients. Together, these results suggest that fulvestrant targets ER+ breast cancer more effectively than tamoxifen even in the presence of estradiol, mainly by attenuation of the innate immune response. Significance: These findings demonstrate novel effects of the pure antiestrogen fulvestrant in ERthorn breast cancer and evaluate its effects under physiologic levels of estradiol, representative of premenopausal patients.

  • 2.
    Aglago, Elom K.
    et al.
    Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom.
    Kim, Andre
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Lin, Yi
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Qu, Conghui
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Evangelou, Marina
    Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom.
    Ren, Yu
    Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom.
    Morrison, John
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Albanes, Demetrius
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, Liberia.
    Arndt, Volker
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Barry, Elizabeth L.
    Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
    Baurley, James W.
    Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
    Berndt, Sonja I.
    Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, MD, Bethesda, Liberia.
    Bien, Stephanie A.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Bishop, D Timothy
    Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
    Bouras, Emmanouil
    Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
    Brenner, Hermann
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Buchanan, Daniel D.
    Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, VIC, Parkville, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, VIC, Parkville, Australia; Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, VIC, Parkville, Australia.
    Budiarto, Arif
    Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia; Computer Science Department, School of Computer Science, Bina Nusantara University, Jakarta, Indonesia.
    Carreras-Torres, Robert
    ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, Girona, Spain.
    Casey, Graham
    Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, VA, Charlottesville, United States.
    Cenggoro, Tjeng Wawan
    Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
    Chan, Andrew T.
    Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, MA, Boston, United States; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States.
    Chang-Claude, Jenny
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
    Chen, Xuechen
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
    Conti, David V.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Devall, Matthew
    Department of Family Medicine, University of Virginia, VA, Charlottesville, United States.
    Diez-Obrero, Virginia
    ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain; Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
    Dimou, Niki
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Drew, David
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States.
    Figueiredo, Jane C.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States; Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, CA, Los Angeles, United States.
    Gallinger, Steven
    Lunenfeld Tanenbaum Research Institute, University of Toronto, Mount Sinai Hospital, ON, Toronto, Canada.
    Giles, Graham G.
    Cancer Epidemiology Division, Cancer Council Victoria, VIC, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, VIC, Clayton, Australia.
    Gruber, Stephen B.
    Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center.
    Gsur, Andrea
    Center for Cancer Research, Medical University of Vienna, Vienna, Austria.
    Gunter, Marc J.
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Hampel, Heather
    Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hidaka, Akihisa
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Harrison, Tabitha A.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Hoffmeister, Michael
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Huyghe, Jeroen R.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Jenkins, Mark A.
    Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
    Jordahl, Kristina
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Joshi, Amit D.
    Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, MA, Boston, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States.
    Kawaguchi, Eric S.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Keku, Temitope O.
    Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, United States.
    Kundaje, Anshul
    Department of Genetics, Stanford University, CA, Stanford, United States; Department of Computer Science, Stanford University, CA, Stanford, United States.
    Larsson, Susanna C.
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Marchand, Loic Le
    University of Hawaii Cancer Center, HI, Honolulu, United States.
    Lewinger, Juan Pablo
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Li, Li
    Department of Family Medicine, University of Virginia, VA, Charlottesville, United States.
    Lynch, Brigid M.
    Cancer Epidemiology Division, Cancer Council Victoria, VIC, Melbourne, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Physical Activity Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia.
    Mahesworo, Bharuno
    Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
    Mandic, Marko
    Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany.
    Obón-Santacana, Mireia
    ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
    Moreno, Victor
    ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
    Murphy, Neil
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Nan, Hongmei
    Department of Epidemiology, Richard M. Fairbanks School of Public Health, IN, Indianapolis, United States; IU Melvin and Bren Simon Cancer Center, Indiana University, IN, Indianapolis, United States.
    Nassir, Rami
    Department of Pathology, School of Medicine, Umm Al-Qura'a University, Mecca, Saudi Arabia.
    Newcomb, Polly A.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington School of Public Health, WA, Seattle, United States.
    Ogino, Shuji
    Broad Institute of Harvard and MIT, MA, Cambridge, United States; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, MA, Boston, United States; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, MA, Boston, United States; Department of Oncologic Pathology, Dana-Farber Cancer Institute, MA, Boston, United States.
    Ose, Jennifer
    Huntsman Cancer Institute, UT, Salt Lake City, United States; Department of Population Health Sciences, University of Utah, UT, Salt Lake City, United States.
    Pai, Rish K.
    Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, AZ, Scottsdale, United States.
    Palmer, Julie R.
    Department of Medicine, Boston University School of Medicine, Slone Epidemiology Center, Boston University, MA, Boston, United States.
    Papadimitriou, Nikos
    Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    Pardamean, Bens
    Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
    Peoples, Anita R.
    Huntsman Cancer Institute, UT, Salt Lake City, United States; Department of Population Health Sciences, University of Utah, UT, Salt Lake City, United States.
    Platz, Elizabeth A.
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, Liberia.
    Potter, John D.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington School of Public Health, WA, Seattle, United States; Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
    Prentice, Ross L.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Rennert, Gad
    Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; Clalit National Cancer Control Center, Haifa, Israel.
    Ruiz-Narvaez, Edward
    Department of Nutritional Sciences, University of Michigan School of Public Health, MI, Ann Arbor, United States.
    Sakoda, Lori C.
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Division of Research, Kaiser Permanente Northern California, CA, Oakland, United States.
    Scacheri, Peter C.
    Department of Genetics and Genome Sciences, Case Western Reserve University, OH, Cleveland, United States.
    Schmit, Stephanie L.
    Genomic Medicine Institute, Cleveland Clinic, OH, Cleveland, United States.
    Schoen, Robert E.
    Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, PA, Pittsburgh, United States.
    Shcherbina, Anna
    Department of Genetics, Stanford University, CA, Stanford, United States; Department of Computer Science, Stanford University, CA, Stanford, United States.
    Slattery, Martha L.
    Department of Internal Medicine, University of Utah, UT, Salt Lake City, United States.
    Stern, Mariana C.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Su, Yu-Ru
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Tangen, Catherine M.
    SWOG Statistical Center, Fred Hutchinson Cancer Research Center, WA, Seattle, United States.
    Thibodeau, Stephen N.
    Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, MN, Rochester, United States.
    Thomas, Duncan C.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Tian, Yu
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; School of Public Health, Capital Medical University, Beijing, China.
    Ulrich, Cornelia M.
    Huntsman Cancer Institute, UT, Salt Lake City, United States; Department of Population Health Sciences, University of Utah, UT, Salt Lake City, United States.
    van Duijnhoven, Franzel Jb
    Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM). Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Visvanathan, Kala
    Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, MD, Baltimore, Liberia.
    Vodicka, Pavel
    Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic.
    Wang, Jun
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    White, Emily
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington School of Public Health, WA, Seattle, United States.
    Wolk, Alicja
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Woods, Michael O.
    Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
    Wu, Anna H.
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Zemlianskaia, Natalia
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Hsu, Li
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Biostatistics, University of Washington, WA, Seattle, United States.
    Gauderman, W James
    Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, CA, Los Angeles, United States.
    Peters, Ulrike
    Public Health Sciences Division, Fred Hutchinson Cancer Research Center, WA, Seattle, United States; Department of Epidemiology, University of Washington School of Public Health, WA, Seattle, United States.
    Tsilidis, Konstantinos K.
    Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, United Kingdom; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
    Campbell, Peter T.
    Department of Epidemiology and Population Health, Albert Einstein College of Medicine, NY, Bronx, United States.
    A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk2023In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 83, no 15, p. 2572-2583Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.

    SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

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  • 3. Aguilo, Francesca
    et al.
    Zhou, Ming-Ming
    Walsh, Martin J
    Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression.2011In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 71, no 16Article in journal (Refereed)
    Abstract [en]

    Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF-INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF-INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b-ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development.

  • 4.
    Akesson, Agneta
    et al.
    Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-17177 Stockholm, Sweden..
    Julin, Bettina
    Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-17177 Stockholm, Sweden..
    Wolk, Alicja
    Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-17177 Stockholm, Sweden..
    Long-term dietary cadmium intake and postmenopausal endometrial cancer incidence: A population-based prospective cohort study2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 15, p. 6435-6441Article in journal (Refereed)
    Abstract [en]

    Environmental pollutants mimicking the effects of estrogen are suggested to contribute to the high incidence of hormone-related cancers, but supporting data are sparse. A potent estrogen-like activity of the pollutant cadmium, mediated via the estrogen receptor-alpha, has been shown in vivo. We prospectively examined the association between cadmium exposure and incidence of postmenopausal endometrial cancer. The Swedish Mammography Cohort is a population-based prospective cohort of 30,210 postmenopausal women free of cancer diagnose at baseline (1987) and who completed a food frequency questionnaire at baseline and in 1997. We estimated the dietary cadmium intake based on the questionnaire data and the cadmium content in all foods. During 16.0 years (484,274 person-years) of follow-up between the baseline and mid-2006, we ascertained 378 incident cases of endometrioid adenocarcinoma. The average estimated dietary cadmium intake was 15 mu g/day (80% from cereals and vegetables). Cadmium intake was statistically significantly associated with increased risk of endometrial cancer in all women; the multivariate relative risk (1111) was 1.39 [95% confidence interval (CI), 1.04-1.86; P-trend = 0.019], comparing highest tertile versus lowest. Among never-smoking women with body mass index (BMI) of <27 kg/m(2), the RR was 1.86 (95% CI, 1.13-3.08; P-trend = 0.009). We observed a 2.9-fold increased risk (95% CI, 1.05-7.79) associated with long-term cadmium intake consistently above the median at both baseline 1987 and in 1997 in never-smoking women with low bioavailable estrogen (BMI of <27 kg/m(2) and nonusers of postmenopausal hormones). Our results support the hypothesis that cadmium may exert estrogenic effects and thereby increase the risk of hormone-related cancers.

  • 5. Akhoondi, Shahab
    et al.
    Sun, Dahui
    von der Lehr, Natalie
    Apostolidou, Sophia
    Klotz, Kathleen
    Maljukova, Alena
    Cepeda, Diana
    Fiegl, Heidi
    Dofou, Dimitra
    Marth, Christian
    Mueller-Holzner, Elisabeth
    Corcoran, Martin
    Dagnell, Markus
    Nejad, Sepideh Zabihi
    Nayer, Babak Noori
    Zali, Mohammad Reza
    Hansson, Johan
    Egyhazi, Susanne
    Petersson, Fredrik
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Grander, Dan
    Reed, Steven I
    Widschwendter, Martin
    Sangfelt, Olle
    Spruck, Charles
    FBXW7/hCDC4 is a general tumor suppressor in human cancer2007In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 67, no 19, p. 9006-9012Article in journal (Refereed)
    Abstract [en]

    The ubiquitin-proteasome system is a major regulatory pathway of protein degradation and plays an important role in cellular division. Fbxw7 (or hCdc4), a member of the F-box family of proteins, which are substrate recognition components of the multisubunit ubiquitin ligase SCF (Skpl-Cdc53/ Cullin-F-box-protein), has been shown to mediate the ubiquitin-dependent proteolysis of several oncoproteins including cyclin El, c-Myc, c-Jun, and Notch. The oncogenic potential of Fbxw7 substrates, frequent allelic loss in human cancers, and demonstration that mutation of FBXW7 cooperates with p53 in mouse tumorigenesis have suggested that Fbxw7 could function as a tumor suppressor in human cancer. Here, we carry out an extensive genetic screen of primary tumors to evaluate the role of FBXW7 as a tumor suppressor in human tumorigenesis. Our results indicate that FBXW7 is inactivated by mutation in diverse human cancer types with an overall mutation frequency of ∼ 6%. The highest mutation frequencies were found in tumors of the bile duct (cholangio-carcinomas, 35%), blood (T-cell acute lymphocytic leukemia, 31%), endometrium (9%), colon (9%), and stomach (6%). Approximately 43% of all mutations occur at two mutational "hotspots," which alter Arg residues (Arg465 and Arg479) that are critical for substrate recognition. Furthermore, we show that Fbxw7Arg465 hotspot mutant can abrogate wild-type Fbxw7 function through a dominant negative mechanism. Our study is the first comprehensive screen of FBXW7 mutations in various human malignancies and shows that FBXW7 is a general tumor suppressor in human cancer.

  • 6.
    Akre [Fall], Katja
    et al.
    Department of Medical Epidemiology, Karolinska Institute, Stockholm.
    Signorello, Lisa B.
    Engstrand, Lars
    Bergström, Reinhold
    Larsson, Sune
    Eriksson, Bengt I.
    Nyrén, Olof
    Risk for gastric cancer after antibiotic prophylaxis in patients undergoing hip replacement2000In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 60, no 22, p. 6376-80Article in journal (Refereed)
    Abstract [en]

    Despite strong evidence of an association between Helicobacter pylori and gastric cancer, the benefit of eradicating H. pylori infection is unknown. Our aim was to test the hypothesis that exposure to high doses of antibiotics reduces risk for gastric cancer via possible eradication of H. pylori We conducted a nationwide case-control study nested in a cohort of 39,154 patients who underwent hip replacement surgery between 1965 and 1983. Such patients frequently receive prophylactic antibiotic treatment. During follow-up through 1989, we identified 189 incident cases of gastric cancer. For each case, three controls were selected from the cohort. Exposure data were abstracted from hospital records. Blood samples from a separate cohort undergoing hip replacement surgery were analyzed for anti-H. pylori IgG before and after surgery. Both long-term antibiotic treatment before surgery [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.7] and prophylactic antibiotic treatment (OR, 0.7; 95% CI, 0.5-1.1) conferred a reduction in gastric cancer risk. The reduction appeared stronger after 5 years (OR, 0.6; 95% CI, 0.3-1.2) than during shorter follow-up after hip replacement (OR, 0.8; 95% CI, 0.4-1.7). There was an apparent decrease in risk with increasing body weight-adjusted doses of antibiotics (P = 0.13). However, the rate of H. pylori antibody disappearance was not strikingly higher in the cohort of patients undergoing hip replacement than in a control cohort. Our findings provide indirect support for the hypothesis that treatment with antibiotics at a relatively advanced age reduces the risk of gastric cancer.

  • 7. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Jansen, Eugene
    van Duijnhoven, Franzel J. B.
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Riboli, Elio
    Gunter, Marc J.
    Westphal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Buckland, Genevieve
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Menendez, Virginia
    Peeters, Petra H.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Allen, Naomi E.
    Crowe, Francesca L.
    Khaw, Kay-Tee
    Wareham, Nickolas
    Pischon, Tobias
    Leptin and soluble leptin receptor in risk of colorectal cancer in the European prospective investigation into Cancer and nutrition cohort2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 20, p. 5328-5337Article in journal (Refereed)
    Abstract [en]

    Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P-trend = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P-trend = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P-trend = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P-trend = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. Cancer Res; 72(20); 5328-37. (C) 2012 AACR.

  • 8.
    Ali, Zaheer
    et al.
    BioReperia AB, Linköping, Sweden.
    Nilsson, Anna
    BioReperia AB, Linköping, Sweden.
    Vildevall, Malin
    BioReperia AB, Linköping, Sweden.
    Rizzo, Larissa
    BioReperia AB, Linköping, Sweden.
    Huge, Ylva
    Region Östergötland, Norrköping, Sweden.
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Fahlgren, Anna
    BioReperia AB, Linköping, Sweden.
    Jensen, Lasse DE
    BioReperia AB, Linköping, Sweden.
    Abstract 6124: Translation of zebrafish tumor-derived xenograft-models for improved diagnosis and treatment planning in urinary bladder cancer patients2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 6 Supplement, p. 6124-6124Article in journal (Refereed)
    Abstract [en]

    Precision medicine in oncology aims to identify the most effective treatment for any given patient based on individualized analyses of patient material. Currently, precision medicine relies on sequencing of DNA or RNA to identify patient tumor-specific mutational profiles that may be coupled to drug response. These techniques, however, fail to reveal actionable mutations in approximately 85% of the cancer patients, and have not been established at all for many commonly used drugs including cisplatin-based treatments used in urinary bladder cancer. While mouse-PDX models can determine drug response rates with high accuracy in most patients and for most drugs, such techniques are too slow and expensive to be relevant for first line treatment planning. Urinary bladder cancer patients are often treated with cisplatin-containing combination therapy, with the hope of down-staging tumors before surgery. 60%, however, do not respond or even progress on this treatment, and these patients would benefit from immediate surgery upon diagnosis. To help identify non-responding patients, we show here that patient-derived tumor xenograft models can be established in zebrafish larvae (ZTX models) and that the resulting tumors exhibit differential responses to the two main cisplatin-containing treatments GC and MVAC.Preliminary results from the first 19 patients are presented. Two tumor biopsies were destroyed during transport and two did not allow isolation of sufficient viable cells for implantation. From the remaining 15 samples an average of 2,6 million cells with average viability of 53% were isolated and used to implant at least 60 2-days old larvae. All 15 samples implanted in the larvae and survived and/or grew exhibiting varying degrees of metastatic dissemination (average between 2 and 13 metastasized cells per embryo and model) within only three days from implantation. Four ZTX models exhibited different responses to GC and MVAC demonstrating that these treatments are not equally effective in all patients. Non-response in ZTX models was associated with tumors having re-appeared in the bladder upon radical cystectomy in all patients undergoing surgery prior to Dec. 5th 2019 (n=3). GC inhibited metastasis in all models (average 69% inhibition), whereas MVAC inhibited metastasis in 40% of the models (average 36% inhibition).In conclusion: The ZTX urinary bladder cancer platform presented here overcome limitations associated with long assay time and high cost of other functional models within precision medicine as well as the low hit-rate of actionable mutations associated with genomic techniques. ZTX models will therefore likely become a powerful method for functional precision medicine within oncology, in the near future.

  • 9. Anantharaman, Devasena
    et al.
    Gheit, Tarik
    Waterboer, Tim
    Halec, Gordana
    Carreira, Christine
    Abedi-Ardekani, Behnoush
    McKay-Chopin, Sandrine
    Zaridze, David
    Mukeria, Anush
    Szeszenia-Dabrowska, Neonila
    Lissowska, Jolanta
    Mates, Dana
    Janout, Vladimir
    Foretova, Lenka
    Bencko, Vladimir
    Rudnai, Peter
    Fabianova, Eleonora
    Tjonneland, Anne
    Travis, Ruth C
    Boeing, Heiner
    Quiros, J Ramon
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Krogh, Vittorio
    Bueno-de-Mesquita, H Bas
    Kotanidou, Anastasia
    Clavel-Chapelon, Francoise
    Weiderpass, Elisabete
    Johansson, Mattias
    Pawlita, Michael
    Scelo, Ghislaine
    Tommasino, Massimo
    Brennan, Paul
    No causal association identified for human papillomavirus infections in lung cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3525-3534Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer. (C) 2014 AACR.

  • 10. Andersson, Torbjörn
    et al.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Lindgren, PG
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Effects of Interferon on Tumor Tissue Content in Liver Metastases of Human Carcinoid Tumors1990In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, no 50, p. 3413-3415Article in journal (Refereed)
    Abstract [en]

    In 21 patients ultrasound-guided cutting biopsies, from carcinoid metastases of the liver, were taken before and after therapy with α-interferon. Each biopsy was examined under light microscopy and the amount of tumor tissue and connective tissue was quantified and then correlated to objective response to interferon therapy. A significant reduction of the amount of tumor tissue, in spite of unaltered metastatic size and a corresponding increase in connective tissue, was seen after interferon therapy. A more pronounced reduction of tumor tissue occurred after long-term interferon therapy. A positive correlation between objective therapy response and tumor tissue reduction was also present. Patients responding poorly, or not at all, to therapy did not show any significant decrease in tumor tissue.

    Since treatment with immune response modifiers is expected to increase in the near future, it is important to choose the right investigations for therapy monitoring, and since all patients in this investigation had unchanged tumor size on repeated radiological examinations, it is obvious that microscopic examination of core biopsies is a better method for evaluating effects of long-term therapy than tumor size measurement with radiological techniques. Further, the results may indicate that interferon exerts a cytotoxic effect on carcinoid tumor cells in vivo.

  • 11. Antoniou, A. C.
    et al.
    Beesley, J.
    McGuffog, L.
    Sinilnikova, O. M.
    Healey, S.
    Neuhausen, S. L.
    Ding, Y. C.
    Rebbeck, T. R.
    Weitzel, J. N.
    Lynch, H. T.
    Isaacs, C.
    Ganz, P. A.
    Tomlinson, G.
    Olopade, O. I.
    Couch, F. J.
    Wang, X.
    Lindor, N. M.
    Pankratz, V. S.
    Radice, P.
    Manoukian, S.
    Peissel, B.
    Zaffaroni, D.
    Barile, M.
    Viel, A.
    Allavena, A.
    Dall'Olio, V.
    Peterlongo, P.
    Szabo, C. I.
    Zikan, M.
    Claes, K.
    Poppe, B.
    Foretova, L.
    Mai, P. L.
    Greene, M. H.
    Rennert, G.
    Lejbkowicz, F.
    Glendon, G.
    Ozcelik, H.
    Andrulis, I. L.
    Thomassen, M.
    Gerdes, A. -M
    Sunde, L.
    Cruger, D.
    Jensen, U. B.
    Caligo, M.
    Friedman, E.
    Kaufman, B.
    Laitman, Y.
    Milgrom, R.
    Dubrovsky, M.
    Cohen, S.
    Borg, A.
    Jernström, H.
    Lindblom, A.
    Rantala, J.
    Stenmark-Askmalm, M.
    Melin, B.
    Nathanson, K.
    Domchek, S.
    Jakubowska, A.
    Lubinski, J.
    Huzarski, T.
    Osorio, A.
    Lasa, A.
    Durán, M.
    Tejada, M. -I
    Godino, J.
    Benitez, J.
    Hamann, U.
    Kriege, M.
    Hoogerbrugge, N.
    Van Der Luijt, R. B.
    Van Asperen, C. J.
    Devilee, P.
    Meijers-Heijboer, E. J.
    Blok, M. J.
    Aalfs, C. M.
    Hogervorst, F.
    Rookus, M.
    Cook, M.
    Oliver, C.
    Frost, D.
    Conroy, D.
    Evans, D. G.
    Lalloo, F.
    Pichert, G.
    Davidson, R.
    Cole, T.
    Cook, J.
    Paterson, J.
    Hodgson, S.
    Morrison, P. J.
    Porteous, M. E.
    Walker, L.
    Kennedy, M. J.
    Dorkins, H.
    Peock, S.
    Godwin, A. K.
    Stoppa-Lyonnet, D.
    De Pauw, A.
    Mazoyer, S.
    Bonadona, V.
    Lasset, C.
    Dreyfus, H.
    Leroux, D.
    Hardouin, A.
    Berthet, P.
    Faivre, L.
    Loustalot, C.
    Noguchi, T.
    Sobol, H.
    Rouleau, E.
    Nogues, C.
    Frénay, M.
    Vénat-Bouvet, L.
    Hopper, J. L.
    Daly, M. B.
    Terry, M. B.
    John, E. M.
    Buys, S. S.
    Yassin, Y.
    Miron, A.
    Goldgar, D.
    Singer, C. F.
    Dressler, A. C.
    Gschwantler-Kaulich, D.
    Pfeiler, G.
    Hansen, T. V. O.
    Jnson, L.
    Agnarsson, B. A.
    Kirchhoff, T.
    Offit, K.
    Devlin, V.
    Dutra-Clarke, A.
    Piedmonte, M.
    Rodriguez, G. C.
    Wakeley, K.
    Boggess, J. F.
    Basil, J.
    Schwartz, P. E.
    Blank, S. V.
    Toland, A. E.
    Montagna, M.
    Casella, C.
    Imyanitov, E.
    Tihomirova, L.
    Blanco, I.
    Lazaro, C.
    Ramus, S. J.
    Sucheston, L.
    Karlan, B. Y.
    Gross, J.
    Schmutzler, R.
    Wappenschmidt, B.
    Engel, C.
    Meindl, A.
    Lochmann, M.
    Arnold, N.
    Heidemann, S.
    Varon-Mateeva, R.
    Niederacher, D.
    Sutter, C.
    Deissler, H.
    Gadzicki, D.
    Preisler-Adams, S.
    Kast, K.
    Schönbuchner, I.
    Caldes, T.
    De La Hoya, M.
    Aittomäki, K.
    Nevanlinna, H.
    Simard, J.
    Spurdle, A. B.
    Holland, H.
    Chen, X.
    Platte, R.
    Chenevix-Trench, G.
    Easton, D. F.
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: Implications for risk prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10-11 - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 12.
    Antoniou, Antonis C.
    et al.
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Beesley, Jonathan
    Queensland Institute of Medical Research, Brisbane, Australia.
    McGuffog, Lesley
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    M. Sinilnikova, Olga
    Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    L. Neuhausen, Susan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    R. Rebbeck, Timothy
    University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA.
    N. Weitzel, Jeffrey
    City Hope Natl Med Centre, Duarte, CA 91010 USA.
    T. Lynch, Henry
    Creighton University, Omaha, NE 68178 USA.
    Isaacs, Claudine
    A. Ganz, Patricia
    University Calif Los Angeles, Jonsson Comprehens Canc Centre, Los Angeles, CA 90024 USA.
    Tomlinson, Gail
    University Texas Hlth Science Centre San Antonio, San Antonio, TX 78229 USA.
    I. Olopade, Olufunmilayo
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    J. Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    M. Lindor, Noralane
    Mayo Clin, Department Med Genet, Rochester, MN USA.
    S. Pankratz, Vernon
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy.
    Viel, Alessandra
    IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy.
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy.
    DallOlio, Valentina
    Cogentech, Consortium Genom Technology, Milan, Italy.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    I. Szabo, Csilla
    Mayo Clin, Coll Med, Department Lab Med and Pathol, Rochester, MN USA.
    Zikan, Michal
    Charles University Prague, Fac Med 1, Department Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, Kathleen
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Poppe, Bruce
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Foretova, Lenka
    Masaryk Mem Canc Institute, Department Canc Epidemiol and Genet, Brno, Czech Republic.
    L. Mai, Phuong
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    H. Greene, Mark
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    Rennert, Gad
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Lejbkowicz, Flavio
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Glendon, Gord
    OCGN, Toronto, ON, Canada.
    Ozcelik, Hilmi
    Mt Sinai Hospital, Fred A Litwin Centre Canc Genet, Samuel Lunenfeld Research Institute, New York, NY 10029 USA.
    L. Andrulis, Irene
    OCGN, Toronto, ON, Canada.
    Thomassen, Mads
    Odense University Hospital, Department Clin Genet, DK-5000 Odense, Denmark.
    Gerdes, Anne-Marie
    Rigshosp, Department Clin Genet, Odense, Denmark.
    Sunde, Lone
    Aalborg Hospital, Department Clin Genet, Aalborg, Denmark.
    Cruger, Dorthe
    Vejle Hospital, Department Clin Genet, Velje, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Department Clin Genet, DK-8000 Aarhus, Denmark.
    Caligo, Maria
    University Pisa, Div Surg Mol and Ultrastruct Pathol, Department Oncol, Pisa, Italy.
    Friedman, Eitan
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Kaufman, Bella
    Sheba Med Centre, Institute Oncol, Tel Hashomer, Israel.
    Laitman, Yael
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Milgrom, Roni
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Dubrovsky, Maya
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Cohen, Shimrit
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden.
    Jernstroem, Helena
    Lund University, Department Oncol, Lund, Sweden.
    Lindblom, Annika
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Rantala, Johanna
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umea University, Department Radiat Science, Umea, Sweden.
    Nathanson, Kate
    University Penn, Philadelphia, PA 19104 USA.
    Domchek, Susan
    University Penn, Philadelphia, PA 19104 USA.
    Jakubowska, Ania
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Lubinski, Jan
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Huzarski, Tomasz
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Osorio, Ana
    Spanish Natl Canc Research Centre, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Genet Serv, Barcelona, Spain.
    Duran, Mercedes
    University Valladolid, Institute Biol and Mol Genet, IBGM UVA, Valladolid, Spain.
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain.
    Godino, Javier
    University Lozano Blesa, Hospital Clin, Oncol Serv, Zaragoza, Spain.
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany.
    Kriege, Mieke
    Daniel Denhoed Canc Centre, Erasmus MC, Department Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University Nijmegen, Nijmegen Med Centre, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands.
    B. van der Luijt, Rob
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands.
    J. van Asperen, Christi
    Leiden University, Med Centre, Department Clin Genet, Leiden, Netherlands.
    Devilee, Peter
    Leiden University, Department Human Genet, Med Centre, Department Pathol, NL-2300 RA Leiden, Netherlands.
    J. Meijers-Heijboer, E.
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands.
    J. Blok, Marinus
    University Med Centre, Department Genet and Cell Biol, Maastricht, Netherlands.
    M. Aalfs, Cora
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands.
    Hogervorst, Frans
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands.
    Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands.
    Cook, Margaret
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Oliver, Clare
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Frost, Debra
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Conroy, Don
    University Cambridge, Department Oncol, Cambridge, England.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, London, England.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet, Glasgow, Lanark, Scotland.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England.
    Cook, Jackie
    Sheffield Childrens Hospital, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Paterson, Joan
    Addenbrookes Hospital, Department Clin Genet, E Anglian Reg Genet Serv, Cambridge, England.
    Hodgson, Shirley
    University London, Department Clin Genet, St Georges Hospital, London, England.
    J. Morrison, Patrick
    Belfast City Hospital, Northern Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim, North Ireland.
    E. Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland.
    Walker, Lisa
    Churchill Hospital, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
    John Kennedy, M.
    St James Hospital, Canc Genet Program, Hope Directorate, Dublin, Ireland.
    Dorkins, Huw
    Kennedy Galton Centre, NW Thames Reg Genet Serv, Harrow, Middx, England.
    Peock, Susan
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    K. Godwin, Andrew
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    Stoppa-Lyonnet, Dominique
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    de Pauw, Antoine
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    Mazoyer, Sylvie
    University Lyon 1, CNRS, Centre Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France.
    Bonadona, Valerie
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Lasset, Christine
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Dreyfus, Helene
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Hardouin, Agnes
    Centre Francois Baclesse, F-14021 Caen, France.
    Berthet, Pascaline
    Centre Francois Baclesse, F-14021 Caen, France.
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France.
    Loustalot, Catherine
    Centre Lutte Canc Georges Francois Leclerc, Dijon, France.
    Noguchi, Tetsuro
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Sobol, Hagay
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Rouleau, Etienne
    Centre Rene Huguenin, INSERM, U735, St Cloud, France.
    Nogues, Catherine
    Frenay, Marc
    Centre Antoine Lacassagne, F-06054 Nice, France.
    Venat-Bouvet, Laurence
    Centre Hospital University Limoges, Department Oncol, Limoges, France.
    L. Hopper, John
    University Melbourne, Melbourne, Vic, Australia.
    B. Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    B. Terry, Mary
    Columbia University, New York, NY USA.
    M. John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA.
    S. Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA.
    Yassin, Yosuf
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Miron, Alexander
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT USA.
    F. Singer, Christian
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Catharina Dressler, Anne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Pfeiler, Georg
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    V. O. Hansen, Thomas
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    Jnson, Lars
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    A. Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland.
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Devlin, Vincent
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, Marion
    Roswell Pk Canc Institute, GOG Stat and Data Centre, Buffalo, NY 14263 USA.
    C. Rodriguez, Gustavo
    NorthShore University Hlth Syst, Evanston NW Healthcare, Evanston, IL USA.
    Wakeley, Katie
    Tufts University, New England Med Centre, Boston, MA 02111 USA.
    F. Boggess, John
    University N Carolina, Chapel Hill, NC USA.
    Basil, Jack
    St Elizabeth Hospital, Edgewood, KY USA.
    E. Schwartz, Peter
    Yale University, Sch Med, New Haven, CT USA.
    V. Blank, Stephanie
    NYU, Sch Med, New York, NY USA.
    Ewart Toland, Amanda
    Ohio State University, Centre Comprehens Canc, Department Internal Med and Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA.
    Montagna, Marco
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Casella, Cinzia
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Riga, Latvia.
    Blanco, Ignacio
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    Lazaro, Conxi
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    J. Ramus, Susan
    University London Imperial Coll Science Technology and Med, Gynaecol Oncol Unit, UCL EGA Institute Womens Hlth, London, England.
    Sucheston, Lara
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA.
    Y. Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Gross, Jenny
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Schmutzler, Rita
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Wappenschmidt, Barbara
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Engel, Christoph
    University Leipzig, Institute Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, Alfons
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Lochmann, Magdalena
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Arnold, Norbert
    University Kiel, Department Obstet and Gynaecol, University Hospital Schleswig Holstein, Kiel, Germany.
    Heidemann, Simone
    University Kiel, Institute Human Genet, University Hospital Schleswig Holstein, Kiel, Germany.
    Varon-Mateeva, Raymonda
    Campus Virchow Klinikum, Charite Berlin, Institute Human Genet, Berlin, Germany.
    Niederacher, Dieter
    University Dusseldorf, Department Obstet and Gynaecol, Div Mol Genet, University Hospital Dusseldorf, Dusseldorf, Germany.
    Sutter, Christian
    University Heidelberg, Institute Human Genet, Div Mol Diagnost, Heidelberg, Germany.
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany.
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany.
    Preisler-Adams, Sabine
    University Hospital Muenster, Institute Human Genet, Munster, Germany.
    Kast, Karin
    Tech University Dresden, Department Obstet and Gynaecol, University Hospital Carl Gustav Carus, Dresden, Germany.
    Schoenbuchner, Ines
    University Wurzburg, Institute Human Genet, Div Med Genet, Wurzburg, Germany.
    Caldes, Trinidad
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, Helsinki, Finland.
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland.
    Simard, Jacques
    Centre Hospital University Quebec, Canada Research Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada.
    B. Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Platte, Radka
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Chenevix-Trench, Georgia
    Queensland Institute of Medical Research, Brisbane, Australia.
    F. Easton, Douglas
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

  • 13. Antoniou, Antonis C.
    et al.
    Beesley, Jonathan
    McGuffog, Lesley
    Sinilnikova, Olga M.
    Healey, Sue
    Neuhausen, Susan L.
    Ding, Yuan Chun
    Rebbeck, Timothy R.
    Weitzel, Jeffrey N.
    Lynch, Henry T.
    Isaacs, Claudine
    Ganz, Patricia A.
    Tomlinson, Gail
    Olopade, Olufunmilayo I
    Couch, Fergus J.
    Wang, Xianshu
    Lindor, Noralane M.
    Pankratz, Vernon S
    Radice, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Barile, Monica
    Viel, Alessandra
    Allavena, Anna
    Dall'Olio, Valentina
    Peterlongo, Paolo
    Szabo, Csilla I
    Zikan, Michal
    Claes, Kathleen
    Poppe, Bruce
    Foretova, Lenka
    Mai, Phuong L.
    Greene, Mark H.
    Rennert, Gad
    Lejbkowicz, Flavio
    Glendon, Gord
    Ozcelik, Hilmi
    Andrulis, Irene L.
    Thomassen, Mads
    Gerdes, Anne-Marie
    Sunde, Lone
    Cruger, Dorthe
    Birk Jensen, Uffe
    Caligo, Maria
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Dubrovsky, Maya
    Cohen, Shimrit
    Borg, Ake
    Jernström, Helena
    Lindblom, Annika
    Rantala, Johanna
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Nathanson, Kate
    Domchek, Susan
    Jakubowska, Ania
    Lubinski, Jan
    Huzarski, Tomasz
    Osorio, Ana
    Lasa, Adriana
    Durán, Mercedes
    Tejada, Maria-Isabel
    Godino, Javier
    Benitez, Javier
    Hamann, Ute
    Kriege, Mieke
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, E J
    Blok, Marinus J
    Aalfs, Cora M
    Hogervorst, Frans
    Rookus, Matti
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Conroy, Don
    Evans, D Gareth
    Lalloo, Fiona
    Pichert, Gabriella
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Hodgson, Shirley
    Morrison, Patrick J
    Porteous, Mary E
    Walker, Lisa
    Kennedy, M John
    Dorkins, Huw
    Peock, Susan
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    de Pauw, Antoine
    Mazoyer, Sylvie
    Bonadona, Valérie
    Lasset, Christine
    Dreyfus, Hélène
    Leroux, Dominique
    Hardouin, Agnès
    Berthet, Pascaline
    Faivre, Laurence
    Loustalot, Catherine
    Noguchi, Tetsuro
    Sobol, Hagay
    Rouleau, Etienne
    Nogues, Catherine
    Frénay, Marc
    Vénat-Bouvet, Laurence
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Dressler, Anne Catharina
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Hansen, Thomas V O
    Jønson, Lars
    Agnarsson, Bjarni A
    Kirchhoff, Tomas
    Offit, Kenneth
    Devlin, Vincent
    Dutra-Clarke, Ana
    Piedmonte, Marion
    Rodriguez, Gustavo C
    Wakeley, Katie
    Boggess, John F
    Basil, Jack
    Schwartz, Peter E
    Blank, Stephanie V
    Toland, Amanda Ewart
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, Evgeny
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Schmutzler, Rita
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Lochmann, Magdalena
    Arnold, Norbert
    Heidemann, Simone
    Varon-Mateeva, Raymonda
    Niederacher, Dieter
    Sutter, Christian
    Deissler, Helmut
    Gadzicki, Dorothea
    Preisler-Adams, Sabine
    Kast, Karin
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Simard, Jacques
    Spurdle, Amanda B
    Holland, Helene
    Chen, Xiaoqing
    Platte, Radka
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 14. Antoniou, Antonis C
    et al.
    Beesley, Jonathan
    McGuffog, Lesley
    Sinilnikova, Olga M
    Healey, Sue
    Neuhausen, Susan L
    Ding, Yuan Chun
    Rebbeck, Timothy R
    Weitzel, Jeffrey N
    Lynch, Henry T
    Isaacs, Claudine
    Ganz, Patricia A
    Tomlinson, Gail
    Olopade, Olufunmilayo I
    Couch, Fergus J
    Wang, Xianshu
    Lindor, Noralane M
    Pankratz, Vernon S
    Radice, Paolo
    Manoukian, Siranoush
    Peissel, Bernard
    Zaffaroni, Daniela
    Barile, Monica
    Viel, Alessandra
    Allavena, Anna
    Dall'Olio, Valentina
    Peterlongo, Paolo
    Szabo, Csilla I
    Zikan, Michal
    Claes, Kathleen
    Poppe, Bruce
    Foretova, Lenka
    Mai, Phuong L
    Greene, Mark H
    Rennert, Gad
    Lejbkowicz, Flavio
    Glendon, Gord
    Ozcelik, Hilmi
    Andrulis, Irene L
    Thomassen, Mads
    Gerdes, Anne-Marie
    Sunde, Lone
    Cruger, Dorthe
    Birk Jensen, Uffe
    Caligo, Maria
    Friedman, Eitan
    Kaufman, Bella
    Laitman, Yael
    Milgrom, Roni
    Dubrovsky, Maya
    Cohen, Shimrit
    Borg, Åke
    Jernström, Helena
    Lindblom, Annika
    Rantala, Johanna
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nathanson, Kate
    Domchek, Susan
    Jakubowska, Ania
    Lubinski, Jan
    Huzarski, Tomasz
    Osorio, Ana
    Lasa, Adriana
    Durán, Mercedes
    Tejada, Maria-Isabel
    Godino, Javier
    Benitez, Javier
    Hamann, Ute
    Kriege, Mieke
    Hoogerbrugge, Nicoline
    van der Luijt, Rob B
    van Asperen, Christi J
    Devilee, Peter
    Meijers-Heijboer, EJ
    Blok, Marinus J
    Aalfs, Cora M
    Hogervorst, Frans
    Rookus, Matti
    Cook, Margaret
    Oliver, Clare
    Frost, Debra
    Conroy, Don
    Evans, D Gareth
    Lalloo, Fiona
    Pichert, Gabriella
    Davidson, Rosemarie
    Cole, Trevor
    Cook, Jackie
    Paterson, Joan
    Hodgson, Shirley
    Morrison, Patrick J
    Porteous, Mary E
    Walker, Lisa
    Kennedy, M John
    Dorkins, Huw
    Peock, Susan
    Godwin, Andrew K
    Stoppa-Lyonnet, Dominique
    de Pauw, Antoine
    Mazoyer, Sylvie
    Bonadona, Valérie
    Lasset, Christine
    Dreyfus, Hélène
    Leroux, Dominique
    Hardouin, Agnès
    Berthet, Pascaline
    Faivre, Laurence
    Loustalot, Catherine
    Noguchi, Tetsuro
    Sobol, Hagay
    Rouleau, Etienne
    Nogues, Catherine
    Frénay, Marc
    Vénat-Bouvet, Laurence
    Hopper, John L
    Daly, Mary B
    Terry, Mary B
    John, Esther M
    Buys, Saundra S
    Yassin, Yosuf
    Miron, Alexander
    Goldgar, David
    Singer, Christian F
    Dressler, Anne Catharina
    Gschwantler-Kaulich, Daphne
    Pfeiler, Georg
    Hansen, Thomas VO
    Jønson, Lars
    Agnarsson, Bjarni A
    Kirchhoff, Tomas
    Offit, Kenneth
    Devlin, Vincent
    Dutra-Clarke, Ana
    Piedmonte, Marion
    Rodriguez, Gustavo C
    Wakeley, Katie
    Boggess, John F
    Basil, Jack
    Schwartz, Peter E
    Blank, Stephanie V
    Toland, Amanda Ewart
    Montagna, Marco
    Casella, Cinzia
    Imyanitov, Evgeny
    Tihomirova, Laima
    Blanco, Ignacio
    Lazaro, Conxi
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Schmutzler, Rita
    Wappenschmidt, Barbara
    Engel, Christoph
    Meindl, Alfons
    Lochmann, Magdalena
    Arnold, Norbert
    Heidemann, Simone
    Varon-Mateeva, Raymonda
    Niederacher, Dieter
    Sutter, Christian
    Deissler, Helmut
    Gadzicki, Dorothea
    Preisler-Adams, Sabine
    Kast, Karin
    Schönbuchner, Ines
    Caldes, Trinidad
    de la Hoya, Miguel
    Aittomäki, Kristiina
    Nevanlinna, Heli
    Simard, Jacques
    Spurdle, Amanda B
    Holland, Helene
    Chen, Xiaoqing
    Platte, Radka
    Chenevix-Trench, Georgia
    Easton, Douglas F
    Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03-1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01-1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10(-11) - 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers.

  • 15. Arroyo, Vidal M.
    et al.
    Lupo, Philip J.
    Melin, Beatrice S.
    Umeå University.
    Styring, Emelie
    Zaikova, Olga
    Papworth, Karin
    Umeå University.
    Soft tissue sarcoma clinical presentation, treatment, and survival in adolescents and young adults compared to older adults: A report from the Scandinavian Sarcoma Group2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 13Article in journal (Other academic)
    Abstract [en]

    Background: Five-year survival rates for those diagnosed with soft tissue sarcoma (STS) have improved significantly among children and older adults (OAs), but these same trends have not been observed for adolescents and young adults (AYAs). While these disparities could be due to differences in biology or treatment, few studies have evaluated STS occurrence and outcome in AYAs. Therefore, the purpose of this study was to evaluate differences between adolescents and young adults (AYAs) and older adults (OAs) diagnosed with STS by stratifying analysis by: (1) clinical presentation; (2) treatment; and (3) survival.

    Methods: Data were obtained from the Scandinavian Sarcoma Group (SSG) Central Register, which includes information on 5,747 patients from Sweden and Norway, diagnosed with a STS during 1986-2011. Variables included: age at diagnosis, metastasis at diagnosis, tumor size, histology, adjuvant treatment, date of death or last follow-up. AYAs were defined as those diagnosed ages 15-39 years. Categorical variables were analyzed using chi-square tests, and continuous variables were analyzed using t-tests. Overall survival (OS) and recurrence-free survival (RFS) were compared between AYAs and OAs using Kaplan-Meier estimates and log-rank tests. All analyses were conducted overall and by common STS subtypes.

    Results: Overall and by STS subtype, there were significant differences between AYAs and OAs on presentation, treatment, and survival. The distribution of STS subtypes was different between OAs and AYAs. For example, OAs were more likely to be diagnosed with leiomyosarcoma compared to AYAs (18% vs. 10%, p<0.001), whereas AYAs were more likely to be diagnosed with malignant peripheral nerve sheath tumor (MPNST, 9% vs. 4%, p<0.001). OAs were also more likely to have larger tumors (>5 cm, 67% vs. 52%, p<0.001) and higher malignancy grade (grade IV, 45% vs. 31%, p<0.001). Interestingly, AYAs were more likely to be treated with radiotherapy and chemotherapy compared to OAs (12% vs. 5%, p<0.001). There were also differences within STS subtypes. For example, OAs were more likely to have metastasis compared to AYAs if diagnosed with leiomyosarcoma (18% vs. 10%, p=0.04). In most scenarios AYAs had significantly better OS and RFS compared to OAs, other than for MPNST (OS: p=0.19, RFS: p=0.28).

    Conclusions: There were several differences between AYAs and OAs on STS presentation, treatment, and outcome. AYAs not only had differences in terms of STS subtypes but also tumor size and malignancy grade within subtypes. Additional work is needed to characterize the biology underlying these differences, which will inform future treatment strategies for both AYAs and OAs with STS.

  • 16. Atkins, Isabelle
    et al.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Il'yasova, Dora
    Armstrong, Georgina N.
    Eckel-Passow, Jeanette E.
    Schoemaker, Minouk J.
    Nothen, Markus M.
    Barnholtz-Sloan, Jill S.
    Swerdlow, Anthony J.
    Simon, Matthias
    Rajaraman, Preetha
    Chanock, Stephen J.
    Shildkraut, Joellen
    Bernstein, Jonine L.
    Hoffman, Per
    Jockel, Karl-Heinz
    Lai, Rose K.
    Claus, Elizabeth B.
    Olson, Sara H.
    Johansen, Christoffer
    Wrensch, Margaret R.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jenkins, Robert B.
    Sanson, Marc
    Bondy, Melissa L.
    Houlston, Richard S.
    Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 8, p. 2065-2071Article in journal (Refereed)
    Abstract [en]

    Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 x 10(-6), candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 x 10(-6)). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis.

    Significance: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

  • 17. Aust, Gabriela
    et al.
    Eichler, Wolfram
    Laue, Sandy
    Lehmann, Irina
    Heldin, Nils-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Lotz, Oliver
    Scherbaum, Werner A.
    Dralle, Henning
    Hoang-Vu, Cuong
    CD97: A dedifferentiation marker in human thyroid carcinomas1997In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 57, no 9, p. 1798-1806Article in journal (Refereed)
    Abstract [en]

    CD97 is a dimeric glycoprotein of Mr 75,000-85,000 and 28,000 belonging to a novel subfamily of seven-span transmembrane region leukocyte cell surface molecules. It is expressed abundantly in cells of hematopoietic origin. This is the first report demonstrating the expression of CD97 outside the hematopoetic system. CD97 was studied in normal human and neoplastic follicular epithelium of the thyroid and anaplastic (n = 3) and papillary (n = 1) thyroid carcinoma cell lines. In normal thyroid tissue (n = 11), no immunoreactivity of CD97 could be found, whereas in differentiated thyroid carcinomas (n = 10), CD97 expression was either lacking or low. Eleven of 12 undifferentiated anaplastic carcinomas revealed high CD97 presentation. CD97 was absent or only weakly present in patients with postoperative T1 tumors but increased greatly with the progression to postoperative T4 tumors. CD97 is clearly present in thyroid carcinoma cell lines but only at a very low level in normal human thyrocytes. Quantitation of CD97 cell surface expression levels revealed that C 643 and SW 1736 cells showed a two to four times higher specific antibody-binding capacity than did 8505 C and HTh 74 cells and a nearly 20 times higher specific antibody-binding capacity than normal thyrocytes. Phorbol 12-myristate 13-acetate treatment progressively caused a decrease of CD97 antigen expression in all cell lines to about 30% of their initial levels after 48 h. Immunohistochemical staining of SW 1736 cells revealed that CD97 is located in most of the cell compartments and suggested a CD97 internalization process after phorbol 12-myristate 13-acetate treatment. Semiquantitative reverse transcription-PCR showed a correlation of CD97 mRNA and cell surface CD97 expression level in the cell lines. SW 1736, HTh 74, and 8505 C cells apparently expressed CD97 with alternative glycosylation compared to peripheral lymphocytes, whereas most of the CD97 antigen presented on thyrocytes and C 643 cells had glycosylation sites resembling those of lymphocytes. The data suggest that CD97 expression may be a sensitive marker of dedifferentiation and of lymph node involvement in human thyroid tumors.

  • 18. Baranov, Vladimir
    et al.
    Yeung, Moorix Mo-Wai
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Expression of carcinoembryonic antigen and nonspecific cross-reacting 50-kDa antigen in human normal and cancerous colon mucosa: comparative ultrastructural study with monoclonal antibodies1994In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 54, no 12, p. 3305-3314Article in journal (Refereed)
    Abstract [en]

    The precise localization of carcinoembryonic antigen (CEA) and non-specific cross-reacting 50-kDa antigen (NCA 50) in normal colon mucosa and colon adenocarcinoma was investigated by using an indirect immunoperoxidase electron microscopic technique with specific monoclonal antibodies. In normal adult colon both antigens were localized to microvesicles and filaments of the "fuzzy coat" on the apical surface of the epithelial cells. In addition, NCA 50 was found in the narrow spaces between adjoining microvilli. Mature columnar cells at the free luminal surface contained most of the antigen positive material. CEA and NCA 50 were also detected as intracellular components of goblet cells. In multilayered tumor glands, the cell surface expression of the antigens was dependent on the position of the tumor cell in the gland. The neoplastic cells showed either a predominant apical labeling or a positive staining of almost the entire cell surface. Some of the neoplastic cells contained CEA in so-called "intracellular lumina." In contrast to normal colon epithelial cells most tumor cells synthesized NCA 50 actively. In normal colonic mucosa, unlike in cancerous tissue, CEA and NCA 50 appear to be released via vesicles formed from the microvillous membrane of mature columnar cells. These results are consistent with the hypothesis that CEA and NCA play a role in the nonspecific defense against microorganisms in the large intestine.

  • 19.
    Baranowska-Kortylewicz, Janina
    et al.
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Abe, Michio
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Pietras, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Kortylewicz, Zbigniew P
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Kurizaki, Takashi
    Department of Surgery II, National Hospital Organization, Kumamoto University Medical School, Kumamoto, Japan.
    Nearman, Jessica
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Paulsson, Janna
    Department of Pathology-Oncology, Karolinska Institute, Stockholm, Sweden.
    Mosley, R Lee
    Departments of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska.
    Enke, Charles A
    Departments of Radiation Oncology, University of Nebraska Medical Center, Omaha, Nebraska.
    Östman, Arne
    Department of Pathology-Oncology, Karolinska Institute, Stockholm, Sweden.
    Effect of platelet-derived growth factor receptor-beta inhibition with STI571 on radioimmunotherapy2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 17, p. 7824-7831Article in journal (Refereed)
    Abstract [en]

    Whereas radioimmunotherapy of hematologic malignancies has evolved into a viable treatment option, the responses of solid tumors to radioimmunotherapy are discouraging. The likely cause of this problem is the interstitial hypertension inherent to all solid tumors. Remarkable improvements in tumor responses to radioimmunotherapy were discovered after the inclusion of STI571 in the therapy regimen. A combination of the tumor stroma-reactive STI571, a potent platelet-derived growth factor receptor-beta (PDGFr-beta) antagonist, and the tumor-seeking radiolabeled antibody B72.3 yielded long-lasting growth arrest of the human colorectal adenocarcinoma LS174T grown as s.c. xenografts in athymic mice. The interaction of STI571 with the stromal PDGFr-beta reduced tumor interstitial fluid pressure (P(IF)) by >50% and in so doing improved the uptake of B72.3. The attenuation of P(IF) also had a positive effect on the homogeneity of antibody distribution. These effects were dose-dependent and under optimized dosing conditions allowed for a 2.45 times increase in the tumor uptake of B72.3 as determined in the biodistribution studies. Single-photon emission computed tomography imaging studies substantiated these results and indicated that the homogeneity of the radioisotope distribution was also much improved when compared with the control mice. The increased uptake of radioimmunotherapy into the tumor resulted in >400% increase in the tumor absorbed radiation doses in STI571 + radioimmunotherapy-treated mice compared with PBS + radioimmunotherapy-treated mice. The improved antibody uptake in response to the attenuation of tumor P(IF) was identified as the primary reason for the growth arrest of the STI571 + radioimmunotherapy-treated tumors. Two related causes were also identified: (a) the improved homogeneity of monoclonal antibody distribution in tumor and (b) the increased tumor radiosensitivity resulting from the improved tumor oxygenation.

  • 20. Barton, Maria
    et al.
    Santucci-Pereira, Julia
    de Cicco, Ricardo Lopez
    Russo, Irma H.
    Ross, Eric A.
    Slifker, Michael
    Peri, Suraj
    Bordas, Pal
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Toniolo, Paolo
    Russo, Jose
    Long noncoding RNAs in the postmenopausal breast and their role in cancer prevention2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 21.
    Bekele, Maheteme
    et al.
    St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.
    Jibril, Aisha
    St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.
    Seifu, Daniel
    Addis Ababa University, Addis Ababa, Ethiopia.
    Abebe, Markos
    Armauer Hansen Research Institute, Addis Ababa, Ethiopia.
    Bekele, Abebe
    Addis Ababa University, Addis Ababa, Ethiopia.
    Tigneh, Wondemagegnhu
    Addis Ababa University, Addis Ababa, Ethiopia.
    Bokretsion, Yonas
    Addis Ababa University, Addis Ababa, Ethiopia.
    Karlsson, Christina
    Örebro University, School of Health Sciences.
    Karlsson, Mats
    Örebro University, School of Medical Sciences.
    Martini, Rachel
    Weill Cornell Medical College, New York NY, USA.
    Elemento, Olivier
    Weill Cornell Medical College, New York NY, USA.
    Yates, Clayton
    Tuskegee University, Tuskegee AL, USA.
    Ginter, Paula
    Weill Cornell Medical College, New York NY, USA.
    Newman, Lisa
    Weill Cornell Medical College, New York NY, USA.
    Davis, Melissa
    Weill Cornell Medical College, New York NY, USA.
    Gebregzabher, Endale Hadgu
    St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia.
    Tumor and immune cell profiling in breast cancer using highly multiplexed imaging mass cytometry single-cell technology demonstrates tumor heterogeneity and immune phenotypic abnormality in Ethiopian women2020In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 80, no 21 Suppl., article id PO-087Article in journal (Other academic)
    Abstract [en]

    Background: Tumor heterogeneity represents a complex challenge to cancer treatment, disease recurrence, and patient survival. Imaging mass cytometry (IMC) is an emerging proteomic tool for cancer profiling in tumor tissue samples. IMC enables digital image analysis by multiplexed immunostaining of cells and proteins within tissue and preserves spatial relations within tumor environment. We have applied IMC based approach to study the heterogeneity of invasive breast carcinoma protein expression pattern in formalin fixed paraffin embedded tissues.

    Methods: A total of 10 region of interest (ROI) derived from 5 patients with primary invasive breast carcinoma representing three molecular subclasses (HR+/HER2-,HER2+/HR- and TNBC) were stained with a 30-marker IMC metal labeled antibody panel (α-SMA, EGFR, p53, CD33, CD16, CD163, CD11b, PDL1, CD31, CD45, D44,Vimentin, FoxP3, CD4, ECadherin, CD68, CD20, CD8a, Cytokeratin7, PD1, GranzymeB, Ki67, ColTypeI, CD3, CD45RO, HLADR, DARC & CD11c). Tissue imaging was done by quantifying the abundance of bound antibody with a Hyperion IMC. MCD Viewer was used for visualization purpose and to export raw 16-bit tiff images for segmentation on CellProfiler. Segmentation masks were combined with the individual tiff files to extract single-cell information from each individual image. HistoCAT was applied to perform unbiased clustering of cell populations using the PhenoGraph algorithm and clustered cell populations was overlaid on t-SNE plot. The relative marker expression was used to generate heat-maps and each cluster was manually assigned a phenotype based on its expression profile.

    Results: The t-SNE generated from each ROI revealed different distinct cell populations and we report the presence of diverse tumor and immune cell populations in our samples. The (min, max) number of PhenoGraph clustered tumor cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. Similarly, the (min, max) number of PhenoGraph clustered immune cell populations in HR+/HER2-, HER2+ and TNBC Cases were (5,8) (7,9) and (5,7) respectively. We also document the presence of inter and intra-tumor heterogeniety in expression of PD1 and PDL1 in all the tumor subtypes studied. Additionally, we report a phenotypic abnormality in the immune cell populations identified with dual or triple markers expression of the canonical CD antigens of T-Cells, B-Cells and macrophages.

    Conclusion: The current study demonstrates high-dimensional visualization with the simultaneous analysis of epithelial, immune, and stromal components using IMC can be used to explore cell populations in tumor tissue to quantify tumor heterogeneity or identification of novel clustering patterns that has potential for translational research and clinical practice. Significance: This study presents the potential of Imaging Mass Cytometry and single cell analysis algorithms in multiplex high throughput tumor tissue studies.

  • 22.
    Bendrik, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
    Robertson, Jennifer
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Gauldie, Jack
    Department of Pathology and Molecular Medicine, Centre for Gene Therapeutics McMaster University, Hamilton, Ontario, Canada.
    Dabrosin, Charlotta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology . Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gene transfer of matrix metalloproteinase-9 induces tumor regression of breast cancer in vivo2008In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 68, no 9, p. 3405-3412Article in journal (Refereed)
    Abstract [en]

    Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer.

  • 23.
    Berg, Tracy J.
    et al.
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Marques, Carolina
    CNIO, Sevc Ballesteros Fdn Brain Tumor Grp, Madrid, Spain..
    Pantazopoulou, Vasiliki
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Johansson, Elinn
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    von Stedingk, Kristoffer
    Lund Univ, Dept Pediat, Clin Sci Lund, Lund, Sweden.;Univ Amsterdam, Dept Oncogen, Acad Med Ctr, M1-131, Amsterdam, Netherlands..
    Lindgren, David
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Jeannot, Pauline
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Pietras, Elin J.
    Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark..
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Governa, Valeria
    Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Bengzon, Johan
    Lund Univ, Lund Stem Cell Ctr, Dept Clin Sci, Div Neurosurg, Lund, Sweden..
    Belting, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Lund Univ, Dept Clin Sci, Div Oncol & Pathol, Lund, Sweden..
    Axelson, Hakan
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    Squatrito, Massimo
    CNIO, Sevc Ballesteros Fdn Brain Tumor Grp, Madrid, Spain..
    Pietras, Alexander
    Lund Univ, Dept Lab Med, Div Translat Canc Res, Lund, Sweden..
    The Irradiated Brain Microenvironment Supports Glioma Stemness and Survival via Astrocyte-Derived Transglutaminase 22021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 8, p. 2101-2115Article in journal (Refereed)
    Abstract [en]

    The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naive brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. Significance: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence.

  • 24. Berglund, Erik
    et al.
    Berglund, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Akcakaya, Pinar
    Ghaderi, Mehran
    Dare, Elisabetta
    Berggren, Per-Olof
    Aspinwall, Craig A.
    Lui, Weng-Onn
    Zedenius, Jan
    Larsson, Catharina
    Branstrom, Robert
    Evidence for intracellular calcium-regulated secretion in gastrointestinal stromal tumor.2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 25.
    Best, Myron
    et al.
    VU Medical Center, Amsterdam, Netherlands.
    Sol, Nik
    VU Medical Center, Amsterdam, Netherlands.
    Kooi, Irsan
    VU Medical Center, Amsterdam, Netherlands.
    Nilsson, Jonas
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Westerman, Bart
    VU Medical Center, Amsterdam, Netherlands.
    Yistra, Bauke
    VU Medical Center, Amsterdam, Netherlands.
    Dorsman, Josephine
    VU Medical Center, Amsterdam, Netherlands.
    Smit, Egbert
    VU Medical Center, Amsterdam, Netherlands.
    Verheui, Henk
    VU Medical Center, Amsterdam, Netherlands.
    Reijneveld, Jaap
    VU Medical Center, Amsterdam, Netherlands.
    Tannous, Bakhos
    Massachusetts General Hospital, Boston, MA, USA.
    Wesseling, Pieter
    VU Medical Center, Amsterdam, Netherlands.
    Wurdinger, Thomas
    VU Medical Center, Amsterdam, Netherlands.
    Tumor-educated platelets allow for multiclass liquid biopsy-based diagnosis of cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no Suppl. 15, article id LB-124Article in journal (Other academic)
  • 26. Bjarnadottir, O.
    et al.
    Romero, Q.
    Bendahl, P-O
    Ryden, L.
    Rose, C.
    Loman, N.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology.
    Jirstrom, K.
    Grabau, D.
    Borgquist, S.
    Statin-induced decrease in proliferation depends on HMG-CoA reductase expression in breast cancer2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72Article in journal (Other academic)
  • 27.
    Blattner, Mirjam
    et al.
    Weill Cornell Med Coll, New York NY, USA.
    Lee, Daniel
    Weill Cornell Med Coll, New York NY, USA.
    O'Reilly, Catherine
    Weill Cornell Med Coll, New York NY, USA.
    Park, Kyung
    Weill Cornell Med Coll, New York NY, USA.
    MacDonald, Theresa Y.
    Weill Cornell Med Coll, New York NY, USA.
    Khani, Francesca
    Weill Cornell Med Coll, New York NY, USA.
    Turner, Kevin
    Weill Cornell Med Coll, New York NY, USA.
    Wild, Peter J.
    Univ Zurich Hosp, Zurich, Switzerland.
    Hieronymus, Haley
    Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Sawyers, Charles L.
    Mem Sloan Kettering Canc Ctr, New York NY, USA.
    Tewari, Ashutosh K.
    Weill Cornell Med Coll, New York, USA.
    Moch, Holger
    Univ Zurich Hosp, Zurich, Switzerland.
    Yoon, Ghil Suk
    Sch Med, Kyungpook Natl Univ, Daegu, South Korea.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Fall, Katja
    Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
    Mosquera, Juan Miguel
    Weill Cornell Med Coll, New York NY, USA.
    Robinson, Brian D.
    Weill Cornell Med Coll, New York NY, USA.
    Sboner, Andrea
    Weill Cornell Med Coll, New York NY, USA.
    Barbierie, Christopher E.
    Weill Cornell Med Coll, New York NY, USA.
    Rubin, Mark A.
    Weill Cornell Med Coll, New York NY, USA.
    SPOP mutations in prostate cancer across demographically diverse patient cohorts2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19, article id 2244Article in journal (Other academic)
  • 28.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Lau, Jasmine
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Chen, Justin
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Weiss, William A.
    Swartling, Fredrik J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    A glial origin for medulloblastoma and inhibition of MYCN stabilization2013In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 73, no 8Article in journal (Other academic)
  • 29.
    Bolin, Sara M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lau, Jasmine
    Chen, Justin
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 30.
    Borgenvik, Anna
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Holmberg, Karl O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Zhao, Miao
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rosén, Gabriela
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Hutter, Sonja
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Garancher, Alexandra
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Rahmanto, Aldwin Suryo
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Bergström, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Olsen, Thale Kristin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mainwaring, Oliver
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Sattanino, Damiana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Verbaan, Annemieke D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rusert, Jessica M.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Sundström, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Ballester Bravo, Mar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Dang, Yonglong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wenz, Amelie S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Richardson, Stacey
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Fotaki, Grammatiki
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hill, Rebecca M.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Dubuc, Adrian M.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Kalushkova, Antonia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Remke, Marc
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Čančer, Matko
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer precision medicine.
    Giraud, Geraldine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Chen, Xingqi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular Tools and Functional Genomics.
    Taylor, Michael D.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON, Canada..
    Sangfelt, Olle
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Clifford, Steven C.
    Newcastle Univ Ctr Canc, Wolfson Childhood Canc Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England..
    Schueller, Ulrich
    Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany.;Univ Med Ctr Hamburg Eppendorf, Dept Paediat Hematol & Oncol, Hamburg, Germany.;Res Inst Childrens Canc Ctr Hamburg, Hamburg, Germany..
    Wechsler-Reya, Robert J.
    Sanford Burnham Prebys Med Discovery Inst, Tumor Initiat & Maintenance Program, San Diego, CA USA..
    Weishaupt, Holger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Swartling, Fredrik J.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neurooncology and neurodegeneration.
    Dormant SOX9-Positive Cells Facilitate MYC-Driven Recurrence of Medulloblastoma2022In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 82, no 24, p. 4586-4603Article in journal (Refereed)
    Abstract [en]

    Relapse is the leading cause of death in patients with medulloblas-toma, the most common malignant pediatric brain tumor. A better understanding of the mechanisms underlying recurrence could lead to more effective therapies for targeting tumor relapses. Here, we observed that SOX9, a transcription factor and stem cell/glial fate marker, is limited to rare, quiescent cells in high-risk medulloblastoma with MYC amplification. In paired primary-recurrent patient samples, SOX9-positive cells accumulated in medulloblastoma relapses. SOX9 expression anti-correlated with MYC expression in murine and human medulloblastoma cells. However, SOX9-positive cells were plastic and could give rise to a MYC high state. To follow relapse at the single-cell level, an inducible dual Tet model of medulloblastoma was developed, in which MYC expression was redirected in vivo from treatment-sensitive bulk cells to dormant SOX9-positive cells using doxycycline treatment. SOX9 was essential for relapse initiation and depended on suppression of MYC activity to promote therapy resistance, epithelial-mesenchymal transition, and immune escape. p53 and DNA repair pathways were downregulated in recurrent tumors, whereas MGMT was upregulated. Recurrent tumor cells were found to be sensitive to treatment with an MGMT inhibitor and doxorubicin. These findings suggest that recurrence-specific targeting coupled with DNA repair inhibition comprises a potential therapeutic strategy in patients affected by medulloblastoma relapse.Significance: SOX9 facilitates therapy escape and recurrence in medulloblastoma via temporal inhibition of MYC/MYCN genes, revealing a strategy to specifically target SOX9-positive cells to prevent tumor relapse.

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  • 31. Borgquist, Signe
    et al.
    Zhou, Wenjing
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jirstrom, Karin
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sollie, Thomas
    Sorlie, Therese
    Butt, Saima
    Blomqvist, Carl
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    The prognostic role of HER2 expression in ductal breast carcinoma in situ2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 9, article id P6-13-03Article in journal (Other academic)
  • 32.
    Bovinder Ylitalo, Erik
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordstrand, Annika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Thysell, Elin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jernberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Crnalic, Sead
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bone remodeling in relation to androgen receptor activity in prostate cancer bone metastases2018In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, no 16, p. 50-50Article in journal (Other academic)
  • 33. Boyango, Ilanit
    et al.
    Barash, Uri
    Naroditsky, Inna
    Li, Jin-Ping
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hammond, Edward
    Ilan, Neta
    Vlodavsky, Israel
    Heparanase Cooperates with Ras to Drive Breast and Skin Tumorigenesis2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 16, p. 4504-4514Article in journal (Refereed)
    Abstract [en]

    Heparanase has been implicated in cancer but its contribution to the early stages of cancer development is uncertain. In this study, we utilized nontransformed human MCF10A mammary epithelial cells and two genetic mouse models [Hpa-transgenic (Hpa-Tg) and knockout mice] to explore heparanase function at early stages of tumor development. Heparanase overexpression resulted in significantly enlarged asymmetrical acinar structures, indicating increased cell proliferation and decreased organization. This phenotype was enhanced by coexpression of heparanase variants with a mutant H-Ras gene, which was sufficient to enable growth of invasive carcinoma in vivo. These observations were extended in vivo by comparing the response of Hpa-Tg mice to a classical two-stage 12-dimethylbenz(a)anthracene (DMBA)/12-o-tetradecanoylphorbol-13-acetate (TPA) protocol for skin carcinogenesis. Hpa-Tg mice overexpressing heparanase were far more sensitive than control mice to DMBA/TPA treatment, exhibiting a 10-fold increase in the number and size of tumor lesions. Conversely, DMBA/TPA-induced tumor formation was greatly attenuated in Hpa-KO mice lacking heparanase, pointing to a critical role of heparanase in skin tumorigenesis. In support of these observations, the heparanase inhibitor PG545 potently suppressed tumor progression in this model system. Taken together, our findings establish that heparanase exerts protumorigenic properties at early stages of tumor initiation, cooperating with Ras to dramatically promote malignant development.

  • 34. Bremer, T.
    et al.
    Savala, J.
    Leesman, G.
    Wärnberg, F.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wadsten, Charlotta
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Whitworth, P. W.
    A biologic signature to predict ipsilateral breast event risk at 10 years for early breast cancer2019In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 79, no 4Article in journal (Other academic)
  • 35.
    Brodin, Greger
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    ten Dijke, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Funa, Keiko
    Institute of Anatomy and Cell Biology, Göteborg University, SE-405 30 Göteborg, Sweden.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Increased Smad Expression and Activation are Associated with Apoptosis in Normal and Malignant Prostate after Castration1999In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 59, no 11, p. 2731-2738Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor (TGF)-beta1 is induced in the prostate after castration and has been implicated in apoptosis of epithelial cells during involution. TGF-beta1-mediated receptor activation induces phosphorylation of Smad2 and Smad3, which form complexes with Smad4, that translocate to the nucleus to regulate transcription of target genes. Smad6 and Smad7 antagonize the action of signal-transducing Smads. We have examined the immunohistochemical expression of different Smad molecules in the epithelium of rat ventral prostate before and after castration, in androgen-sensitive Dunning R3327 PAP prostatic tumor cells from untreated and castrated rats, and after treatment with estrogen. In the ventral prostate, a significant increase of phosphorylated Smad2 (P-Smad2) was observed after castration. In prostatic tumor cells we observed an increased expression of Smad2 and P-Smad2 after treatment. The levels of Smad3 and, in particular, Smad4 were enhanced in the normal ventral prostate, as well as in the tumors after castration. Interestingly, Smad6 and Smad7 expression was also up-regulated in cells with increased Smad2 activation. The staining for Smad2, P-Smad2, Smad3, Smad4, and Smad7 was nuclear in some cells and was present in areas with a large number of apoptotic cells identified by various morphological criteria, formation of apoptotic bodies and, in adjacent sections, by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. Our results suggest that the signal transduction pathway for TGF-beta, leading to apoptosis, is activated in the normal prostate after castration and in the tumor model after castration, without or with estrogen treatment.

  • 36. Bruzzese, Francesca
    et al.
    Hagglof, Christina
    Leone, Alessandra
    Sjoberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Hammarsten, Peter
    Egevad, Lars
    Bergh, Anders
    Ostman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. 

  • 37. Bruzzese, Francesca
    et al.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Leone, Alessandra
    Sjöberg, Elin
    Roca, Maria Serena
    Kiflemariam, Sara
    Sjöblom, Tobias
    Hammarsten, Peter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Egevad, Lars
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Östman, Arne
    Budillon, Alfredo
    Augsten, Martin
    Local and systemic protumorigenic effects of cancer-associated fibroblast-derived GDF152014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 13, p. 3408-3417Article in journal (Refereed)
    Abstract [en]

    The tumor stroma is vital to tumor development, progression, and metastasis. Cancer-associated fibroblasts (CAF) are among the abundant cell types in the tumor stroma, but the range of their contributions to cancer pathogenicity has yet to be fully understood. Here, we report a critical role for upregulation of the TGF beta/BMP family member GDF15 (MIC-1) in tumor stroma. GDF15 was found upregulated in situ and in primary cultures of CAF from prostate cancer. Ectopic expression of GDF15 in fibroblasts produced prominent paracrine effects on prostate cancer cell migration, invasion, and tumor growth. Notably, GDF15-expressing fibroblasts exerted systemic in vivo effects on the outgrowth of distant and otherwise indolent prostate cancer cells. Our findings identify tumor stromal cells as a novel source of GDF15 in human prostate cancer and illustrate a systemic mechanism of cancer progression driven by the tumor microenvironment. Further, they provide a functional basis to understand GDF15 as a biomarker of poor prognosis and a candidate therapeutic target in prostate cancer. (C)2014 AACR.

  • 38. Bräutigam, Lars
    et al.
    Pudelko, Linda
    Jemth, Ann-Sofie
    Gad, Helge
    Narwal, Mohit
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Gustafsson, Robert
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Karsten, Stella
    Carreras Puigvert, Jordi
    Homan, Evert
    Berndt, Carsten
    Warpman Berglund, Ulrika
    Stenmark, Pål
    Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
    Helleday, Thomas
    Hypoxic Signaling and the Cellular Redox Tumor Environment Determine Sensitivity to MTH1 Inhibition2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 8, p. 2366-2375Article in journal (Refereed)
    Abstract [en]

    Cancer cells are commonly in a state of redox imbalance that drives their growth and survival. To compensate for oxidative stress induced by the tumor redox environment, cancer cells upregulate specific nononcogenic addiction enzymes, such as MTH1 (NUDT1), which detoxifies oxidized nucleotides. Here, we show that increasing oxidative stress in nonmalignant cells induced their sensitization to the effects of MTH1 inhibition, whereas decreasing oxidative pressure in cancer cells protected against inhibition. Furthermore, we purified zebrafish MTH1 and solved the crystal structure of MTH1 bound to its inhibitor, highlighting the zebrafish as a relevant tool to study MTH1 biology. Delivery of 8-oxo-dGTP and 2-OH-dATP to zebrafish embryos was highly toxic in the absence of MTH1 activity. Moreover, chemically or genetically mimicking activated hypoxia signaling in zebrafish revealed that pathologic upregulation of the HIF1 alpha response, often observed in cancer and linked to poor prognosis, sensitized embryos to MTH1 inhibition. Using a transgenic zebrafish line, in which the cellular redox status can be monitored in vivo, we detected an increase in oxidative pressure upon activation of hypoxic signaling. Pretreatment with the antioxidant N-acetyl-L-cysteine protected embryos with activated hypoxia signaling against MTH1 inhibition, suggesting that the aberrant redox environment likely causes sensitization. In summary, MTH1 inhibition may offer a general approach to treat cancers characterized by deregulated hypoxia signaling or redox imbalance.

  • 39.
    Buckley, Patrick
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Jarbo, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Menzel, Uwe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Mathiesen, Tiit
    Scott, Carol
    Gregory, Simon
    Langford, Cordelia
    Dumanski, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Comprehensive DNA copy number profiling of meningioma using a chromosome 1 tiling path microarray identifies novel candidate tumor suppressor loci2005In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 65, no 7, p. 2653-2661Article in journal (Refereed)
    Abstract [en]

    Meningiomas are common neoplasms of the meninges lining of the central nervous system. Deletions of 1p have been established as important for the initiation and/or progression of meningioma. The rationale of this array-CGH study was to characterize copy number imbalances of chromosome 1 in meningioma, using a full-coverage genomic microarray containing 2,118 distinct measurement points. In total, 82 meningiomas were analyzed, making this the most detailed analysis of chromosome 1 in a comprehensive series of tumors. We detected a broad range of aberrations, such as deletions and/or gains of various sizes. Deletions were the predominant finding and ranged from monosomy to a 3.5-Mb terminal 1p homozygous deletion. Although multiple aberrations were observed across chromosome 1, every meningioma in which imbalances were detected harbored 1p deletions. Tumor heterogeneity was also observed in three recurrent meningiomas, which most likely reflects a progressive loss of chromosomal segments at different stages of tumor development. The distribution of aberrations supports the existence of at least four candidate loci on chromosome 1, which are important for meningioma tumorigenesis. In one of these regions, our results already allow the analysis of a number of candidate genes. In a large series of cases, we observed an association between the presence of segmental duplications and deletion breakpoints, which suggests their role in the generation of these tumor-specific aberrations. As 1p is the site of the genome most frequently affected by tumor-specific aberrations, our results indicate loci of general importance for cancer development and progression.

  • 40.
    Busch, Susann
    et al.
    Gothenburg University, Sweden.
    Sims, Andrew H.
    University of Edinburgh, Scotland.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Ferno, Marten
    Lund University, Sweden.
    Landberg, Goran
    Gothenburg University, Sweden; University of Manchester, England.
    Loss of TGF beta Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 7, p. 1457-1469Article in journal (Refereed)
    Abstract [en]

    One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease.

  • 41. Caja, Laia
    et al.
    Sancho, Patricia
    Univ Barcelona, Barcelona, Spain.
    Bertran, Esther
    Univ Barcelona, Barcelona, Spain.
    Iglesias-Serret, Daniel
    Univ Barcelona, Barcelona, Spain.
    Gil, Joan
    Univ Barcelona, Barcelona, Spain.
    Fabregat, Isabel
    Univ Barcelona, Barcelona, Spain.
    Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-{beta}-induced cell death through impairing up-regulation of the NADPH oxidase NOX4.2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 19, p. 7595-7602Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-beta in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-beta-induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-beta-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-beta, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-beta and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis.

  • 42. Cedervall, Jessica
    et al.
    Jamil, Seema
    Prasmickaite, Lina
    Cheng, YenFu
    Eskandarpour, Malihe
    Hansson, Johan
    Maelandsmo, Gunhild M.
    Ringborg, Ulrik
    Gulyas, Miklos
    Department of pathology and cytology, central hospital, Gävle, Sweden.
    Zhen, He Suo
    Kanter, Lena
    Ahrlund-Richter, Lars
    Species-specific in vivo engraftment of the human BL melanoma cell line results in an invasive dedifferentiated phenotype not present in xenografts2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 9, p. 3746-3754Article in journal (Refereed)
    Abstract [en]

    For clinically relevant studies on melanoma progression and invasiveness, in vivo experimental systems with a human cellular microenvironment would be advantageous. We have compared tumor formation from a human cutaneous malignant melanoma cell line (BL), after injection as conventional xenografts in the mouse, or when injected into a predominantly species-specific environment of human embryonic stem cell-derived teratoma induced in the mouse (the hEST model). The resulting melanoma histology was generally analogous, both systems showing delimited densely packed areas with pleomorphic cells of malignant appearance. A specificity of the integration process into the human embryonic teratoma tissues was indicated by the melanoma exclusively being found in areas compatible with condensed mesenchyme, similar to neural crest development. Here, also enhanced neovascularization was seen within the human mesenchymal tissues facing the BL melanoma growth. Furthermore, in the hEST model an additional melanoma cell phenotype occurred, located at the border of, or infiltrating into, the surrounding human loose mesenchymal fibrous stroma. This BL population had a desmoplastic spindle-like appearance, with markers indicative of dedifferentiation and migration. The appearance of this apparently more aggressive phenotype, as well as the induction of human angiogenesis, shows specific interactions with the human embryonic microenvironment in the hEST model. In conclusion, these data provide exciting options for using the hEST model in molecular in vivo studies on differentiation, invasiveness, and malignancy of human melanoma, while analyzing species-specific reactions in vivo.

  • 43.
    Cedervall, Jessica
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Huang, Hua
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Zhang, Lei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Femel, Julia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Dimberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Olsson, Anna-Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Neutrophil Extracellular Traps Accumulate in Peripheral Blood Vessels and Compromise Organ Function in Tumor-Bearing Animals2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 13, p. 2653-2662Article in journal (Refereed)
    Abstract [en]

    Cancer produces a variety of collateral effects in patients beyond the malignancy itself, including threats to distal organ functions. However, the basis for such effects, associated with either primary or metastatic tumors, are generally poorly understood. In this study, we show how heart and kidney vascular function is impaired by neutrophils that accumulate in those tissues as a result of tumor formation in two different transgenic mouse models of cancer (RIP1-Tag2 model of insulinoma and MMTV-PyMT model of breast cancer). Neutrophil depletion by systemic administration of an anti-Gr1 antibody improved vascular perfusion and prevented vascular leakage in kidney vessels. We also observed the accumulation of platelet-neutrophil complexes, a signature of neutrophil extracellular traps (NET), in the kidneys of tumor-bearing mice that were completely absent from healthy nontumor-bearing littermates. NET accumulation in the vasculature was associated with upregulation of the proinflammatory adhesion molecules ICAM-1, VCAM-1, and E-selectin, as well as the proinflammatory cytokines IL1 beta, IL6, and the chemokine CXCL1. Administering DNase I to dissolve NETs, which have a high DNA content, restored perfusion in the kidney and heart to levels seen in nontumor-bearing mice, and also prevented vessel leakage in the blood vasculature of these organs. Taken together, our findings strongly suggest that NETs mediate the negative collateral effects of tumors on distal organs, acting to impair vascular function, and to heighten inflammation at these sites.

  • 44.
    Cedervall, Jessica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Yanyu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olsson, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure2016In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 76, no 15, p. 4311-4315Article, review/survey (Refereed)
    Abstract [en]

    A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as amechanismby which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of proteinarginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis.

  • 45. Cha, Shih-Ting
    et al.
    Chen, Pai-Sheng
    Johansson, Gunnar
    1Laboratory of Molecular and Cellular Toxicology, Institute of Toxicology, College of Medicine, National Taiwan University.
    Chu, Chia-Yu
    Wang, Ming-Yang
    Jeng, Yung-Ming
    Yu, Sung-Liang
    Chen, Jin-Shing
    Chang, King-Jen
    Jee, Shiou-Hwa
    Tan, Ching-Ting
    Lin, Ming-Tsan
    Kuo, Min-Liang
    MicroRNA-519c suppresses hypoxia-inducible factor-1alpha expression and tumor angiogenesis.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 7, p. 2675-2685Article in journal (Refereed)
    Abstract [en]

    Hypoxia-inducible factor-1alpha (HIF-1alpha) is widely considered to be one of the key regulators of tumor angiogenesis. The upstream regulation is complex and involves several growth factors, cytokines, and hypoxia. Herein, we have identified miR-519c as a hypoxia-independent regulator of HIF-1alpha, acting through direct binding to the HIF-1alpha 3' untranslated region and leading to reduced tumor angiogenesis. Overexpression of miR-519c resulted in a significant decrease of HIF-1alpha protein levels and reduced the tube formation of human umbilical vein endothelial cells; similarly, antagomir inhibition of miR-519c increased the level of HIF-1alpha protein and enhanced angiogenic activity, suggesting an important role of miR-519c in HIF-1alpha-mediated angiogenesis. Consistent with the overexpression of miR-519c in cancer patients with better prognosis, mice injected with miR-519c-overexpressing cells exhibited dramatically reduced HIF-1alpha levels, followed by suppressed tumor angiogenesis, growth, and metastasis. In addition, we found that hepatocyte growth factor (HGF), a known HIF-1alpha inducer, reduced the miR-519c levels through an Akt-dependent pathway. This regulation was posttranscriptional and may be mediated by suppression of miR-519c maturation. Taken together, our findings provide the first evidence that miR-519c is a pivotal regulator of tumor angiogenesis and that microenvironmental HGF contributes to regulating miR-519c biogenesis in cancer cells.

  • 46. Chan, Norman
    et al.
    Pires, Isabel M
    Bencokova, Zuzana
    Coackley, Carla
    Luoto, Kaisa R
    Bhogal, Nirmal
    Lakshman, Minalini
    Gottipati, Ponnari
    Oliver, F Javier
    Helleday, Thomas
    Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
    Hammond, Ester M
    Bristow, Robert G
    Contextual synthetic lethality of cancer cell kill based on the tumor microenvironment.2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 20, p. 8045-54Article in journal (Refereed)
    Abstract [en]

    Acute and chronic hypoxia exists within the three-dimensional microenvironment of solid tumors and drives therapy resistance, genetic instability, and metastasis. Replicating cells exposed to either severe acute hypoxia (16 hours with 0.02% O(2)) followed by reoxygenation or moderate chronic hypoxia (72 hours with 0.2% O(2)) treatments have decreased homologous recombination (HR) protein expression and function. As HR defects are synthetically lethal with poly(ADP-ribose) polymerase 1 (PARP1) inhibition, we evaluated the sensitivity of repair-defective hypoxic cells to PARP inhibition. Although PARP inhibition itself did not affect HR expression or function, we observed increased clonogenic killing in HR-deficient hypoxic cells following chemical inhibition of PARP1. This effect was partially reversible by RAD51 overexpression. PARP1(-/-) murine embryonic fibroblasts (MEF) showed a proliferative disadvantage under hypoxic gassing when compared with PARP1(+/+) MEFs. PARP-inhibited hypoxic cells accumulated γH2AX and 53BP1 foci as a consequence of altered DNA replication firing during S phase-specific cell killing. In support of this proposed mode of action, PARP inhibitor-treated xenografts displayed increased γH2AX and cleaved caspase-3 expression in RAD51-deficient hypoxic subregions in vivo, which was associated with decreased ex vivo clonogenic survival following experimental radiotherapy. This is the first report of selective cell killing of HR-defective hypoxic cells in vivo as a consequence of microenvironment-mediated "contextual synthetic lethality." As all solid tumors contain aggressive hypoxic cells, this may broaden the clinical utility of PARP and DNA repair inhibition, either alone or in combination with radiotherapy and chemotherapy, even in tumor cells lacking synthetically lethal, genetic mutations.

  • 47.
    Chaudhry, Arvind
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Gobl, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors1994In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 54, no 4, p. 981-986Article in journal (Refereed)
    Abstract [en]

    Endocrine pancreatic tumors are neuroendocrine neoplasms with malignant potential and give rise to varied clinical syndromes due to excessive secretion of multiple hormones. In this study 22 endocrine pancreatic tumors and 11 carcinoid tumors were examined for the expression of CD44 using a monoclonal antibody. CD44 gene activity of 11 endocrine pancreatic tumor tissues and five carcinoid tumor tissues was also studied by amplifying messenger RNA with the polymerase chain reaction followed by electrophoresis and blot hybridization. Strong immunoreactivity was detected on all gastrinomas examined (P < 0.001), and in two non-functioning endocrine pancreatic tumors. Such immunoreactivity was not observed in other subtypes of endocrine pancreatic tumors. In the normal human pancreas, the acinar portion and ductal epithelial cells stained strongly positive but pancreatic islet cells did not show any significant immunostaining. Furthermore, in endocrine pancreatic tumors with metastatic disease, CD44-positive tumors had a tendency to metastasize to lymph nodes (P = 0.005), as compared with CD44-negative tumors which were locally invasive or metastasized to the liver. Although, in this limited material and short follow-up, we were not able to show any statistical significance, patients with CD44-negative endocrine pancreatic tumors had prolonged survival time compared with patients with CD44-positive tumors (73% versus 59% at 5 years; P = 0.7). Of 10 carcinoid tumors examined, all three foregut carcinoids and one midgut carcinoid stained strongly positive, whereas all other midgut carcinoids were negative. Analysis of CD44 splice variants showed that in all five gastrinomas there was overproduction of alternatively spliced larger molecular variants as compared with other types of endocrine pancreatic tumors and carcinoid tumors. The band pattern from one case of carcinoid tumor with a fulminant clinical course was similar to that of gastrinomas, whereas other carcinoid tumors expressed the epithelial form of CD44. The earlier identified splice variants which confer metastatic behavior on a pancreatic tumor cell line were not expressed in neuroendocrine tumors. Our data indicate that CD44 expression in endocrine pancreatic tumors correlates with the ability to give rise to lymph node metastases and may play a vital role in determining the fate of metastasizing cells. Moreover, because gastrin is not detectable in the normal human pancreas, the pancreatic ductal cell positivity for CD44 strengthened the ductal origin concept of gastrinomas. The band pattern of CD44 splice variants suggests that the previously described splice variants conferring metastatic behavior do not accompany metastatic activity of neuroendocrine tumors.

  • 48. Chen, Min-Wei
    et al.
    Hua, Kuo-Tai
    Kao, Hsin-Jung
    Chi, Chia-Chun
    Wei, Lin-Hung
    Johansson, Gunnar
    Graduate Institute of Toxicology, National Taiwan University College of Medicine.
    Shiah, Shine-Gwo
    Chen, Pai-Sheng
    Jeng, Yung-Ming
    Cheng, Tsu-Yao
    Lai, Tsung-Ching
    Chang, Jeng-Shou
    Jan, Yi-Hua
    Chien, Ming-Hsien
    Yang, Chih-Jen
    Huang, Ming-Shyan
    Hsiao, Michael
    Kuo, Min-Liang
    H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 20, p. 7830-7840Article in journal (Refereed)
    Abstract [en]

    G9a is a mammalian histone methyltransferase that contributes to the epigenetic silencing of tumor suppressor genes. Emerging evidence suggests that G9a is required to maintain the malignant phenotype, but the role of G9a function in mediating tumor metastasis has not been explored. Here, we show that G9a is expressed in aggressive lung cancer cells, and its elevated expression correlates with poor prognosis. RNAi-mediated knockdown of G9a in highly invasive lung cancer cells inhibited cell migration and invasion in vitro and metastasis in vivo. Conversely, ectopic G9a expression in weakly invasive lung cancer cells increased motility and metastasis. Mechanistic investigations suggested that repression of the cell adhesion molecule Ep-CAM mediated the effects of G9a. First, RNAi-mediated knockdown of Ep-CAM partially relieved metastasis suppression imposed by G9a suppression. Second, an inverse correlation between G9a and Ep-CAM expression existed in primary lung cancer. Third, Ep-CAM repression was associated with promoter methylation and an enrichment for dimethylated histone H3K9. G9a knockdown reduced the levels of H3K9 dimethylation and decreased the recruitment of the transcriptional cofactors HP1, DNMT1, and HDAC1 to the Ep-CAM promoter. Our findings establish a functional contribution of G9a overexpression with concomitant dysregulation of epigenetic pathways in lung cancer progression.

  • 49.
    Cunha, Sara I.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Bocci, Matteo
    Lovrot, John
    Eleftheriou, Nikolas
    Roswall, Pernilla
    Cordero, Eugenia
    Lindstrom, Linda
    Bartoschek, Michael
    Haller, B. Kristian
    Pearsall, R. Scott
    Mulivor, Aaron W.
    Kumar, Ravindra
    Larsson, Christer
    Bergh, Jonas
    Pietras, Kristian
    Endothelial ALK1 Is a Therapeutic Target to Block Metastatic Dissemination of Breast Cancer2015In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 75, no 12, p. 2445-2456Article in journal (Refereed)
    Abstract [en]

    Exploration of new strategies for the prevention of breast cancer metastasis is justifiably at the center of clinical attention. In this study, we combined a computational biology approach with mechanism-based preclinical trials to identify inhibitors of activin-like receptor kinase (ALK) 1 as effective agents for blocking angiogenesis and metastasis in breast cancer. Pharmacologic targeting of ALK1 provided long-term therapeutic benefit in mouse models of mammary carcinoma, accompanied by strikingly reduced metastatic colonization as a monotherapy or part of combinations with chemotherapy. Gene-expression analysis of breast cancer specimens from a population-based nested case-control study encompassing 768 subjects defined endothelial expression of ALK1 as an independent and highly specific prognostic factor for metastatic manifestation, a finding that was corroborated in an independent clinical cohort. Overall, our results suggest that pharmacologic inhibition of endothelial ALK1 constitutes a tractable strategy for interfering with metastatic dissemination of breast cancer.

  • 50.
    Dagnino, Sonia
    et al.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Bodinier, Barbara
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Guida, Florence
    International Agency for Research on Cancer (IARC), Lyon, France.
    Smith-Byrne, Karl
    International Agency for Research on Cancer (IARC), Lyon, France.
    Petrovic, Dusan
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Department of Epidemiology and Health Systems (DESS), University Center for General Medicine and Public Health (UNISANTE), Lausanne, Switzerland; Department and Division of Primary Care Medicine, University Hospital of Geneva, Geneva, Switzerland.
    Whitaker, Matthew D.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom.
    Nøst, Therese Haugdahl
    Department of Community Medicine, UiT- The Arctic University of Norway, Tromsø, Norway.
    Agnoli, Claudia
    Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Palli, Domenico
    Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
    Sacerdote, Carlotta
    Unit of Cancer Epidemiology, Citta della Salute e della Scienza University-Hospital, Turin, Italy.
    Panico, Salvatore
    Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
    Tumino, Rosario
    Cancer Registry and Histopathology Department, Provincial Health Authority (ASP) Ragusa, Italy.
    Schulze, Matthias B.
    Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Keski-Rahkonen, Pekka
    International Agency for Research on Cancer (IARC), Lyon, France.
    Scalbert, Augustin
    International Agency for Research on Cancer (IARC), Lyon, France.
    Vineis, Paolo
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Italian Institute of Technology, Genova, Italy.
    Johansson, Mattias
    International Agency for Research on Cancer (IARC), Lyon, France.
    Sandanger, Torkjel M.
    Department of Community Medicine, UiT- The Arctic University of Norway, Tromsø, Norway.
    Vermeulen, Roel C.H.
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands.
    Chadeau-Hyam, Marc
    MRC Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom; Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands.
    Prospective identification of elevated circulating CDCP1 in patients years before onset of lung cancer2021In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 81, no 13, p. 3738-3748Article in journal (Refereed)
    Abstract [en]

    Increasing evidence points to a role for inflammation in lung carcinogenesis. A small number of circulating inflammatory proteins have been identified as showing elevated levels prior to lung cancer diagnosis, indicating the potential for prospective circulating protein concentration as a marker of early carcinogenesis. To identify novel markers of lung cancer risk, we measured a panel of 92 circulating inflammatory proteins in 648 prediagnostic blood samples from two prospective cohorts in Italy and Norway (women only). To preserve the comparability of results and protect against confounding factors, the main statistical analyses were conducted in women from both studies, with replication sought in men (Italian participants). Univariate and penalized regression models revealed for the first time higher blood levels of CDCP1 protein in cases that went on to develop lung cancer compared with controls, irrespective of time to diagnosis, smoking habits, and gender. This association was validated in an additional 450 samples. Associations were stronger for future cases of adenocarcinoma where CDCP1 showed better explanatory performance. Integrative analyses combining gene expression and protein levels of CDCP1 measured in the same individuals suggested a link between CDCP1 and the expression of transcripts of LRRN3 and SEM1. Enrichment analyses indicated a potential role for CDCP1 in pathways related to cell adhesion and mobility, such as the WNT/β-catenin pathway. Overall, this study identifies lung cancer–related dysregulation of CDCP1 expression years before diagnosis.

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