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  • 1. Aleksandrova, Krasimira
    et al.
    Chuang, Shu-Chun
    Boeing, Heiner
    Zuo, Hui
    Tell, Grethe S
    Pischon, Tobias
    Jenab, Mazda
    Bueno-de-Mesquita, Bas
    Vollset, Stein Emil
    Midttun, Øivind
    Ueland, Per Magne
    Fedirko, Veronika
    Johansson, Mattias
    Weiderpass, Elisabete
    Severi, Gianluca
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Kühn, Tilman
    Tjønneland, Anne
    Overvad, Kim
    Quirós, J Ramón
    Jakszyn, Paula
    Sánchez, María-José
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Travis, Ruth C
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Sieri, Sabina
    Tumino, Rosario
    Panico, Salvatore
    May, Anne M
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kong, So Yeon J
    Freisling, Heinz
    Gunter, Marc J
    Lu, Yunxia
    Cross, Amanda J
    Riboli, Elio
    Vineis, Paolo
    A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 4, article id djv010Article in journal (Refereed)
    Abstract [en]

    Background: Neopterin may be relevant for colorectal cancer (CRC) development, as a biomarker of cellular immune activity exerting pleiotropic effects on cellular ageing, oxidative stress, and inflammation. So far, the association between prediagnostic neopterin and colon and rectal cancer risk has not been evaluated in human populations. Methods: A nested case-control study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort using data on plasma concentrations of total neopterin (T-N, sum of neopterin and 7,8-dihydroneopterin) in 830 incident CRC case patients (561 colon and 269 rectal) matched within risk sets to 830 control participants. A subsequent replication study used data from the Hordaland Health Study, where 173 CRC case patients have been diagnosed among 6594 healthy participants over 12 years of follow-up. Results: After multivariable adjustment for a priori chosen CRC risk factors, a "U-shaped" association of T-N with CRC was revealed. Compared with the second quintile of the T-N distribution, the relative risks for the first, third, fourth, and fifth quintiles were 2.37 (95% CI = 1.66 to 3.39), 1.24 (95% CI = 0.87 to 1.77), 1.55 (95% CI = 1.08 to 2.22), and 2.31 (95% CI = 1.63 to 3.27), respectively. Replication of these associations within the Hordaland Health Study yielded similar results. No differences have been observed when the associations were explored by colon and rectal cancer site (two-sided P-difference = .87) and after excluding case patients diagnosed within the first four follow-up years. Conclusions: These novel findings provide evidence of the role of both suppressed and activated cell-mediated immunity as reflected by prediagnostic T-N concentrations in the development of CRC.

  • 2. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Fedirko, Veronika
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Duijnhoven, Franzel J. B.
    Jansen, Eugene
    Rinaldi, Sabina
    Romieu, Isabelle
    Ferrari, Pietro
    Murphy, Neil
    Gunter, Marc J.
    Riboli, Elio
    Westhpal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Trichopoulou, Antonia
    Bamia, Christina
    Orfanos, Philippos
    Agnoli, Claudia
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra H.
    Duell, Eric J.
    Molina-Montes, Esther
    Ramon Quiros, J.
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Pischon, Tobias
    Boeing, Heiner
    Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)2014In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 29, no 4, p. 261-275Article in journal (Refereed)
    Abstract [en]

    A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development.

  • 3. Aleksandrova, Krasimira
    et al.
    Pischon, Tobias
    Jenab, Mazda
    Bueno-de-Mesquita, H Bas
    Fedirko, Veronika
    Norat, Teresa
    Romaguera, Dora
    Knüppel, Sven
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Dartois, Laureen
    Kaaks, Rudolf
    Li, Kuanrong
    Tjønneland, Anne
    Overvad, Kim
    Quirós, José Ramón
    Buckland, Genevieve
    Sánchez, María José
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas J
    Bradbury, Kathryn E
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Siersema, Peter D
    Peeters, Petra HM
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ericson, Ulrika
    Ohlsson, Bodil
    Weiderpass, Elisabete
    Skeie, Guri
    Borch, Kristin
    Rinaldi, Sabina
    Romieu, Isabelle
    Kong, Joyce
    Gunter, Marc J
    Ward, Heather A
    Riboli, Elio
    Boeing, Heiner
    Combined impact of healthy lifestyle factors on colorectal cancer: a large European cohort study2014In: BMC Medicine, ISSN 1741-7015, E-ISSN 1741-7015, Vol. 12, no 1, p. 168-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors - healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. RESULTS: After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. CONCLUSIONS: Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.

  • 4. Bamia, Christina
    et al.
    Lagiou, Pagona
    Buckland, Genevieve
    Grioni, Sara
    Agnoli, Claudia
    Taylor, Aliki J.
    Dahm, Christina C.
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Cottet, Vanessa
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Grote, Verena
    Teucher, Birgit
    Boeing, Heiner
    Buijsse, Brian
    Trichopoulos, Dimitrios
    Adarakis, George
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Palli, Domenico
    Bueno-de-Mesquita, H. Bas
    van Duijnhoven, Fraenzel J. B.
    Peeters, Petra H. M.
    Engeset, Dagrun
    Skeie, Guri
    Lund, Eiliv
    Sanchez, Maria-Jose
    Barricarte, Aurelio
    Huerta, Jose-Maria
    Ramon Quiros, J.
    Dorronsoro, Miren
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Drake, Isabel
    Key, Timothy J.
    Khaw, Kay-Tee
    Wareham, Nick
    Romieu, Isabelle
    Fedirko, Veronika
    Jenab, Mazda
    Romaguera, Dora
    Norat, Teresa
    Trichopoulou, Antonia
    Mediterranean diet and colorectal cancer risk: results from a European cohort2013In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 28, no 4, p. 317-328Article in journal (Refereed)
    Abstract [en]

    The authors investigated the association of adherence to Mediterranean diet with colorectal cancer (CRC) risk in the European Prospective Investigation into Cancer and nutrition study. Adherence to Mediterranean diet was expressed through two 10-unit scales, the Modified Mediterranean diet score (MMDS) and the Centre-Specific MMDS (CSMMDS). Both scales share the same dietary components but differ in the cut-off values that were used for these components in the construction of the scales. Adjusted hazard ratios (HR) for the associations of these scales with CRC incidence were estimated. After 5,296,617 person-years of follow-up, 4,355 incident CRC cases were identified. A decreased risk of CRC, of 8 and 11 % was estimated when comparing the highest (scores 6-9) with the lowest (scores 0-3) adherence to CSMMDS and MMDS respectively. For MMDS the HR was 0.89 (95 % confidence interval (CI): 0.80, 0.99). A 2-unit increment in either Mediterranean scale was associated with a borderline statistically significant 3 to 4 % reduction in CRC risk (HR for MMDS: 0.96; 95 % CI: 0.92, 1.00). These associations were somewhat more evident, among women, were mainly manifested for colon cancer risk and their magnitude was not altered when alcohol was excluded from MMDS. These findings suggest that following a Mediterranean diet may have a modest beneficial effect on CRC risk.

  • 5. Bisschop, Charlotte N. Steins
    et al.
    van Gils, Carla H.
    Emaus, Marleen J.
    Bueno-de-Mesquita, H. Bas
    Monninkhof, Evelyn M.
    Boeing, Heiner
    Aleksandrova, Krasmira
    Jenab, Mazda
    Norat, Teresa
    Riboli, Elio
    Boutron-Rualt, Marie-Christine
    Fagherazzi, Guy
    Racine, Antoine
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Naccarati, Alessio
    Mattiello, Amalia
    Vicente Argueeles, Marcial
    Jose Sanchez, Maria
    Jose Tormo, Maria
    Ardanaz, Eva
    Dorronsoro, Miren
    Bonet, Catalina
    Khaw, Kay-Tee
    Key, Tim
    Trichopoulou, Antonia
    Orfanos, Philippos
    Naska, Androniki
    Kaaks, Rudolph R.
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Pischon, Tobias
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirstrom, Karin
    Ohlsson, Bodil
    Overvad, Kim
    Berentzen, Tina Landsvig
    Halkjaer, Jytte
    Tjonneland, Anne
    Weiderpass, Elisabete
    Skeie, Guri
    Braaten, Tonje
    Siersema, Peter D.
    Freisling, Heinz
    Ferrari, Pietro
    Peeters, Petra H. M.
    May, Anne M.
    Weight change later in life and colon and rectal cancer risk in participants in the EPIC-PANACEA study2014In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 99, no 1, p. 139-147Article in journal (Refereed)
    Abstract [en]

    Background: A moderate association exists between body mass index (BMI) and colorectal cancer. Less is known about the effect of weight change. Objective: We investigated the relation between BMI and weight change and subsequent colon and rectal cancer risk. Design: This was studied among 328,781 participants in the prospective European Prospective Investigation into Cancer Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating study (mean age: 50 y). Body weight was assessed at recruitment and on average 5 y later. Self-reported weight change (kg/y) was categorized in sex-specific quintiles, with quintiles 2 and 3 combined as the reference category (men: -0.6 to 0.3 kg/y; women: -0.4 to 0.4 kg/y). In the subsequent years, participants were followed for the occurrence of colon and rectal cancer (median period: 6.8 y). Multivariable Cox proportional hazards regression analyses were used to study the association. Results: A total of 1261 incident colon cancer and 747 rectal cancer cases were identified. ME at recruitment was statistically significantly associated with colon cancer risk in men (HR: 1.04; 95% CI: 1.02, 1.07). Moderate weight gain (quintile 4) in men increased risk further (HR: 1.32; 95% CI: 1.04, 1.68), but this relation did not show a clear trend. In women, BMI or weight gain was not related to subsequent risk of colon cancer. No statistically significant associations for weight loss and colon cancer or for BMI and weight changes and rectal cancer were found. Conclusions: BMI attained at adulthood was associated with colon cancer risk. Subsequent weight gain or loss was not related to colon or rectal cancer risk in men or women.

  • 6. Bradbury, Kathryn E.
    et al.
    Appleby, Paul N.
    Tipper, Sarah J.
    Travis, Ruth C.
    Allen, Naomi E
    Kvaskoff, Marina
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Cervenka, Iris
    Mahamat-Saleh, Yahya
    Bonnet, Fabrice
    Kaaks, Rudolf
    Fortner, Renée T.
    Boeing, Heiner
    Trichopoulou, Antonia
    La Vecchia, Carlo
    Stratigos, Alexander J.
    Palli, Domenico
    Grioni, Sara
    Matullo, Giuseppe
    Panico, Salvatore
    Tumino, Rosario
    Peeters, Petra H.
    Bueno-de-Mesquita, H Bas
    Ghiasvand, Reza
    Veierød, Marit B.
    Weiderpass, Elisabete
    Bonet, Catalina
    Molina, Elena
    Huerta, José M.
    Larrañaga, Nerea
    Barricarte, Aurelio
    Merino, Susana
    Isaksson, Karolin
    Stocks, Tanja
    Ljuslinder, Ingrid
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc J.
    Rinaldi, Sabina
    Tsilidis, Konstantinos K.
    Aune, Dagfinn
    Riboli, Elio
    Key, Timothy J.
    Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 5, p. 957-966Article in journal (Refereed)
    Abstract [en]

    Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.

  • 7. Caini, Saverio
    et al.
    Masala, Giovanna
    Saieva, Calogero
    Kvaskoff, Marina
    Sacerdote, Carlotta
    Savoye, Isabelle
    Hemmingsson, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Bech, Bodil Hammer
    Overvad, Kim
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Mancini, Francesca Romana
    Boutron-Ruault, Marie-Christine
    Cervenka, Iris
    Kaaks, Rudolf
    Kuehn, Tilman
    Boeing, Heiner
    Floegel, Anna
    Trichopoulou, Antonia
    Valanou, Elisavet
    Kritikou, Maria
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Bueno-de-Mesquita, H. B(as)
    Peeters, Petra H.
    Veierod, Marit B.
    Ghiasvand, Reza
    Lukic, Marko
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Salamanca Fernandez, Elena
    Larranaga, Nerea
    Zamora-Ros, Raul
    Nilsson, Lena Maria
    Umeå University, Arctic Research Centre at Umeå University. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Jirstrom, Karin
    Sonestedt, Emily
    Key, Timothy J.
    Wareham, Nick
    Khaw, Kay-Tee
    Gunter, Marc
    Huybrechts, Inge
    Murphy, Neil
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Palli, Domenico
    Coffee, tea and melanoma risk: findings from the European Prospective Investigation into Cancer and Nutrition2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 140, no 10, p. 2246-2255Article in journal (Refereed)
    Abstract [en]

    What's new? Laboratory studies suggest that coffee and tea protect against melanoma, but epidemiological findings are inconsistent. Here the authors studied more than 400,000 participants within the European Prospective Investigation into Cancer and Nutrition (EPIC) and confirmed an inverse association between caffeinated coffee consumption and melanoma risk. No association was found with decaffeinated coffee or tea. Interestingly, drinking coffee only protected men, but not women, from developing the often fatal skin cancer, raising interesting questions about gender-specific hormones or coffee habits influencing this association. In vitro and animal studies suggest that bioactive constituents of coffee and tea may have anticarcinogenic effects against cutaneous melanoma; however, epidemiological evidence is limited to date. We examined the relationships between coffee (total, caffeinated or decaffeinated) and tea consumption and risk of melanoma in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a multicentre prospective study that enrolled over 500,000 participants aged 25-70 years from ten European countries in 1992-2000. Information on coffee and tea drinking was collected at baseline using validated country-specific dietary questionnaires. We used adjusted Cox proportional hazards regression models to calculate hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between coffee and tea consumption and melanoma risk. Overall, 2,712 melanoma cases were identified during a median follow-up of 14.9 years among 476,160 study participants. Consumption of caffeinated coffee was inversely associated with melanoma risk among men (HR for highest quartile of consumption vs. non-consumers 0.31, 95% CI 0.14-0.69) but not among women (HR 0.96, 95% CI 0.62-1.47). There were no statistically significant associations between consumption of decaffeinated coffee or tea and the risk of melanoma among both men and women. The consumption of caffeinated coffee was inversely associated with melanoma risk among men in this large cohort study. Further investigations are warranted to confirm our findings and clarify the possible role of caffeine and other coffee compounds in reducing the risk of melanoma.

  • 8. Chuang, Shu-Chun
    et al.
    Boeing, Heiner
    Vollset, Stein Emil
    Midttun, Oivind
    Ueland, Per Magne
    Bueno-de-Mesquita, Bas
    Lajous, Martin
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Kuehn, Tilman
    Pischon, Tobias
    Drogan, Dagmar
    Tjonneland, Anne
    Overvad, Kim
    Quiros, J. Ramon
    Agudo, Antonio
    Molina-Montes, Esther
    Dorronsoro, Miren
    Maria Huerta, Jose
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nicholas J.
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Agnoli, Claudia
    Tumino, Rosario
    Mattiello, Amalia
    Peeters, Petra H.
    Weiderpass, Elisabete
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gunter, Marc
    Lu, Yunxia
    Cross, Amanda J.
    Riboli, Elio
    Vineis, Paolo
    Aleksandrova, Krasimira
    Cellular immune activity biomarker neopterin is associated hyperlipidemia: results from a large population-based study2016In: Immunity & Ageing, ISSN 1742-4933, E-ISSN 1742-4933, Vol. 13, article id 5Article in journal (Refereed)
    Abstract [en]

    Background: Increased serum neopterin had been described in older age two decades ago. Neopterin is a biomarker of systemic adaptive immune activation that could be potentially implicated in metabolic syndrome (MetS). Measurements of waist circumference, triglycerides, high-density lipoprotein cholesterol (HDLC), systolic and diastolic blood pressure, glycated hemoglobin as components of MetS definition, and plasma total neopterin concentrations were performed in 594 participants recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC).

    Results: Higher total neopterin concentrations were associated with reduced HDLC (9.7 %, p < 0.01 for men and 9.2 %, p < 0.01 for women), whereas no association was observed with the rest of the MetS components as well as with MetS overall (per 10 nmol/L: OR = 1.42, 95 % CI = 0.85-2.39 for men and OR = 1.38, 95 % CI = 0.79-2.43).

    Conclusions: These data suggest that high total neopterin concentrations are cross-sectionally associated with reduced HDLC, but not with overall MetS.

  • 9. Dik, Vincent K
    et al.
    Bueno-de-Mesquita, H Bas
    Van Oijen, Martijn GH
    Siersema, Peter D
    Uiterwaal, Cuno SPM
    Van Gils, Carla H
    Van Duijnhoven, Fränzel JB
    Cauchi, Stéphane
    Yengo, Loic
    Froguel, Philippe
    Overvad, Kim
    Bech, Bodil H
    Tjønneland, Anne
    Olsen, Anja
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Fagherazzi, Guy
    Kühn, Tilman
    Campa, Daniele
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Peppa, Eleni
    Oikonomou, Eleni
    Palli, Domenico
    Grioni, Sara
    Vineis, Paolo
    Tumino, Rosaria
    Panico, Salvatore
    Peeters, Petra HM
    Weiderpass, Elisabete
    Engeset, Dagrun
    Braaten, Tonje
    Dorronsoro, Miren
    Chirlaque, María-Dolores
    Sánchez, María-José
    Barricarte, Aurelio
    Zamora-Ros, Raul
    Argüelles, Marcial
    Jirström, Karin
    Wallström, Peter
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Arctic Research Centre at Umeå University.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Arctic Research Centre at Umeå University.
    Travis, Ruth C
    Khaw, Kay-Tee
    Wareham, Nick
    Freisling, Heinz
    Licaj, Idlir
    Jenab, Mazda
    Gunter, Marc J
    Murphy, Neil
    Romaguera-Bosch, Dora
    Riboli, Elio
    Coffee and tea consumption, genotype based CYP1A2 and NAT2 activity, and colorectal cancer risk: results from the EPIC cohort study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 401-412Article in journal (Refereed)
    Abstract [en]

    Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio's (HR) and 95%-confidence intervals (95%-CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7±8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95%-CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95%-CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95%-CI 0.84-1.11) and tea (HR 0.97, 95%-CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggest that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.

  • 10.
    Edwinsdotter Ardnor, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The BRCA1 exon 13 duplication: clinical characteristics of 22 families in Northern Sweden2019In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 18, no 1, p. 37-42Article in journal (Refereed)
    Abstract [en]

    The clinical management of BRCA1/2 mutation carriers requires accurate cancer risk estimates. Cancer risks vary according to type and location of the mutation and since there is limited information about mutation-specific cancer risks, genotype-phenotype correlation studies are needed. This is a report of 22 families with the same mutation, BRCA1 duplication exon 13, a mutation that is found world-wide, with the objective to describe the cancer history found in these families. We studied 69 confirmed carriers, 53 women and 16 men, and additionally 29 women who were clinically expected carriers. Among the confirmed carriers, 27 women (51%) were diagnosed with breast cancer, 10 (19%) with ovarian cancer, 5 (9%) with breast and ovarian cancer and 17 (32%) without cancer. Nine women (17%) with breast cancer were 35 years or younger at diagnose. Also, two cases of early onset colon cancer were found, and 37,5% of the male carriers were diagnosed with prostate cancer. These data may have implications for risk assessment and cancer prevention decision making for carriers of the BRCA1 duplication exon 13 mutation.

  • 11. Fedirko, Veronika
    et al.
    Romieu, Isabelle
    Aleksandrova, Krasimira
    Pischon, Tobias
    Trichopoulos, Dimitrios
    Peeters, Petra H.
    Romaguera-Bosch, Dora
    Bueno-de-Mesquita, H. B(as)
    Dahm, Christina C.
    Overvad, Kim
    Chirlaque, Maria-Dolores
    Johansen, Christoffer
    Bidstrup, Pernille E.
    Dalton, Susanne O.
    Gunter, Marc J.
    Wark, Petra A.
    Norat, Teresa
    Halkjaer, Jytte
    Tjonneland, Anne
    Dik, Vincent K.
    Siersema, Peter D.
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Bastide, Nadia
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Trichopoulou, Antonia
    Klinaki, Eleni
    Katsoulis, Michalis
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Palli, Domenico
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Sanchez, Maria-Jose
    Barricarte, Aurelio
    Amiano, Pilar
    Ramon Quiros, J.
    Manjer, Jonas
    Jirstroem, Karin
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Bradbury, Kathryn E.
    Stepien, Magdalena
    Duarte-Salles, Talita
    Riboli, Elio
    Jenab, Mazda
    Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 8, p. 1949-1960Article in journal (Refereed)
    Abstract [en]

    General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (FIRS) and corresponding 95% confidence intervals (as). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, prediagnostic BMI kg/m2 was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2). Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% Cl = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% Cl = 1.02-1.16) and allcause death (HR= 1.11, 95% CI= 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis.

  • 12. Glimelius, Bengt
    et al.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Enblad, Gunilla
    Alafuzoff, Irina
    Beskow, Anna
    Ahlström, Håkan
    Bill-Axelson, Anna
    Birgisson, Helgi
    Björ, Ove
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Edqvist, Per-Henrik
    Hansson, Tony
    Helleday, Thomas
    Hellman, Per
    Henriksson, Kerstin
    Hesselager, Göran
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggman, Michael
    Höglund, Martin
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Larsson, Chatarina
    Lindman, Henrik
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Mindus, Stephanie
    Nygren, Peter
    Pontén, Fredrik
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rosenquist, Richard
    Sandin, Fredrik
    Schwenk, Jochen M.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stålberg, Karin
    Stålberg, Peter
    Sundström, Christer
    Thellenberg Karlsson, Camilla
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Westermark, Bengt
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Claesson-Welsh, Lena
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sjöblom, Tobias
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umea Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 13. Hughes, David J
    et al.
    Fedirko, Veronika
    Jenab, Mazda
    Schomburg, Lutz
    Méplan, Catherine
    Freisling, Heinz
    Bueno-de-Mesquita, H B As
    Hybsier, Sandra
    Becker, Niels-Peter
    Czuban, Magdalena
    Tjønneland, Anne
    Outzen, Malene
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Bastide, Nadia
    Kühn, Tilman
    Kaaks, Rudolf
    Trichopoulos, Dimitrios
    Trichopoulou, Antonia
    Lagiou, Pagona
    Panico, Salvatore
    Peeters, Petra H
    Weiderpass, Elisabete
    Skeie, Guri
    Dagrun, Engeset
    Chirlaque, Maria-Dolores
    Sánchez, Maria-Jose
    Ardanaz, Eva
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Bradbury, Kathryn E
    Vineis, Paolo
    Naccarati, Alessio
    Palli, Domenico
    Boeing, Heiner
    Overvad, Kim
    Dorronsoro, Miren
    Jakszyn, Paula
    Cross, Amanda J
    Quirós, Jose Ramón
    Stepien, Magdalena
    Kong, So Yeon
    Duarte-Salles, Talita
    Riboli, Elio
    Hesketh, John E
    Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 5, p. 1149-1161Article in journal (Refereed)
    Abstract [en]

    Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 μg/L and 4.3 mg/L in cases and 85.6 μg/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR = 0.92, 95% CI: 0.82-1.03 per 25 μg/L increase). However, sub-group analyses by sex showed a statistically significant association for women (ptrend  = 0.032; per 25 μg/L Se increase, IRR = 0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (ptrend  = 0.009; per 0.806 mg/L increase, IRR = 0.89, 95% CI: 0.82-0.98) with the association more apparent in women (ptrend  = 0.004; IRR = 0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (ptrend  = 0.485; IRR = 0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.

  • 14.
    Johansson, David
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Kosovac, Eldina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Moharer, Jasmine
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology.
    Behnam-Motlagh, Parviz
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry. Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Expression of verotoxin-1 receptor Gb3 in breast cancer tissue and verotoxin-1 signal transduction to apoptosis: Bacterial toxins, cancer treatment2009In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 26, no 9, p. 67-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The prerequisite for the potential use of the bacterial toxin verotoxin-1 in the treatment of breast cancer was investigated by first determining the expression of its receptor Gb3 (CD77) in clinical breast cancer tissue specimens. We then examined the cytotoxicity and mechanism of apoptosis induction of Escherichia coli verotoxin-1 (VT-1) in two human breast cancer cell lines. METHODS: Immunohistochemistry for Gb3 expression was performed on cryostat section from 25 breast cancer specimens. The human breast cancer cell lines T47D and MCF-7 were screened for Gb3 expression by flow cytometry. Fluorescein diacetate and LDH release was used to determine cell viability after VT-1 exposure. Apoptosis was studied by measuring caspase activity and DNA-fragmentation. Signal transduction studies were performed on T47D cells with immunoblotting. RESULTS: Gb3 expression was detected in the vascular endothelial cells of all tumours specimens, and in tumour cells in 17 of the specimens. We found no associations between tumour cell Gb3-expression and age, tumour size, TNM-classification, histological type, hormone receptor expression, or survival time. T47D cells strongly expressed Gb3 and were sensitive to the cytotoxicity, caspase activation and DNA fragmentation by VT-1, whereas MCF-7 cells with faint Gb3-expression were insensitive to VT-1. VT-1 (0.01 - 5 microg/L) exposure for 72 h resulted in a small percentage of viable T47D cells whereas the cytotoxicity of cells pre-treated with 2 micromol/L D, L-treo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP, an inhibitor of glucosylceramide synthesis) was eliminated (< or = 0.1 microg/L VT-1) or reduced (0.5 - 5 microg/L VT-1). VT-1 did not cause cellular LDH-release or cell cycle arrest. VT-1 induction of caspase-3 (0.1, 1, and 5 microg/L VT-1), -8, and -9 (1 and 5 microg/L VT-1) activity and DNA fragmentation of T47D cells was blocked by PPMP. Key components of MAP kinase signalling pathways that control mitochondrial function were investigated. VT-1 0.1 - 5 microg/L induced phosphorylation of JNK as well as MKK3/6 suggesting that survival signal pathways were overruled by VT-1-induced JNK activation leading to mitochondrial depolarization, caspase-9 activation and apoptosis. CONCLUSION: The high specificity and apoptosis-inducing properties of verotoxin-1 indicates that the toxin potentially may be used for treatment of Gb3-expressing breast cancer.

  • 15. Kreimer, Aimee R.
    et al.
    Brennan, Paul
    Kuhs, Krystle A. Lang
    Waterboer, Tim
    Clifford, Gary
    Franceschi, Silvia
    Michel, Angelika
    Willhauck-Fleckenstein, Martina
    Riboli, Elio
    Castellsague, Xavier
    Hildesheim, Allan
    Fortner, Renee Turzanski
    Kaaks, Rudolf
    Palli, Domenico
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Panico, Salvatore
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Mesrine, Sylvie
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Peeters, Petra H.
    Cross, Amanda J.
    Bueno-de-Mesquita, H. Bas
    Vineis, Paolo
    Larranaga, Nerea
    Pala, Valeria
    Sanchez, Maria-Jose
    Navarro, Carmen
    Barricarte, Aurelio
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Boeing, Heiner
    Steffen, Annika
    Travis, Ruth C.
    Ramon Quiros, J.
    Weiderpass, Elisabete
    Pawlita, Michael
    Johansson, Mattias
    International Agency for Research on Cancer, Lyon, France.
    Human Papillomavirus Antibodies and Future Risk of Anogenital Cancer: A Nested Case-Control Study in the European Prospective Investigation Into Cancer and Nutrition Study2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 8, p. 877-884Article in journal (Refereed)
    Abstract [en]

    Purpose Human papillomavirus (HPV) type 16 (HPV16) causes cancer at several anatomic sites. In the European Prospective Investigation Into Cancer and Nutrition study, HPV16 E6 seropositivity was present more than 10 years before oropharyngeal cancer diagnosis and was nearly absent in controls. The current study sought to evaluate the extent to which HPV16 E6 antibodies are present before diagnosis of anogenital cancers within the same cohort. Methods Four hundred incident anogenital cancers (273 cervical, 24 anal, 67 vulvar, 12 vaginal, and 24 penile cancers) with prediagnostic blood samples (collected on average 3 and 8 years before diagnosis for cervix and noncervix cancers, respectively) and 718 matched controls were included. Plasma was analyzed for antibodies against HPV16 E6 and multiple other HPV proteins and genotypes and evaluated in relation to risk using unconditional logistic regression. Results HPV16 E6 seropositivity was present in 29.2% of individuals (seven of 24 individuals) who later developed anal cancer compared with 0.6% of controls (four of 718 controls) who remained cancer free (odds ratio [OR], 75.9; 95% CI, 17.9 to 321). HPV16 E6 seropositivity was less common for cancers of the cervix (3.3%), vagina (8.3%), vulva (1.5%), and penis (8.3%). No associations were seen for non-type 16 HPV E6 antibodies, apart from anti-HPV58 E6 and anal cancer (OR, 6.8; 95% CI, 1.4 to 33.1). HPV16 E6 seropositivity tended to increase in blood samples drawn closer in time to cancer diagnosis. Conclusion HPV16 E6 seropositivity is relatively common before diagnosis of anal cancer but rare for other HPV-related anogenital cancers.

  • 16. Kyro, C.
    et al.
    Olsen, A.
    Landberg, R.
    Skeie, G.
    Loft, S.
    Aman, P.
    Leenders, M.
    Dik, V.
    Siersema, P.
    Pischon, T.
    Christensen, J.
    Overvad, K.
    Boutron-Ruault, M. C.
    Fagherazzi, G.
    Cottet, V.
    Kuehn, T.
    ChangClaude, J.
    Boeing, H.
    Trichopoulou, A.
    Bamia, C.
    Trichopoulos, D.
    Palli, D.
    Krogh, V.
    Tumino, R.
    Vineis, P.
    Panico, S.
    Peters, P.
    Weiderpass, E.
    Bakken, T.
    Asli, L.
    Argueelles, M.
    Jakszyn, P.
    Sanchez, M. J.
    Castano, J.
    Barricarte, A.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, T.
    Travis, R.
    Ferrari, P.
    Freisling, H.
    Jenab, M.
    Tjonneland, A.
    Bueno-de-Mesquita, B.
    ALKYLRESORCINOLS (BIOMARKERS OF WHOLE-GRAIN INTAKE) AND RISK OF COLORECTAL CANCER IN THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Supplement 1, p. 1207-1208Article in journal (Other academic)
    Abstract [en]

    Background and objectives: Few studies have investigatedthe association between whole-grain intake and colorectal cancer.Whole-grain products are one of the dietary items proneto measurement errors, making the use of objective measures,such as biomarkers, highly relevant. The objective of the studywas to investigate the association between biomarkers ofwhole-grain intake, alkylresorcinols, and colorectal cancer ina nested case-control study within the European ProspectiveInvestigation into Cancer and Nutrition (EPIC). Methods: We included 1372 first incident colorectal cancercases and 1372 individually matched controls and calculatedthe incidence rate ratios (IRR) for overall and sub-sites of colorectalcancer using conditional logistic regression adjusted forpotential confounders.Results: Plasma total alkylresorcinol concentrations werenot associated with risk of overall colorectal cancer, proximalcolon cancer or rectal cancer. However, high plasma total alkylresorcinolconcentrations were statistically significantly associatedwith lower incidence of cancer located in the distal (leftor descending) part of the colon. Adjusted IRR of distal coloncancer for highest versus lowest quartile of plasma alkylresorcinolwas 0.48 (95% confidence interval = 0.28 to 0.83). Furthermore,we observed an inverse association with colon cancerfor the Scandinavian part of the participants. Alkylresorcinolsmay be more appropriate as biomarkers in Middle Europe andScandinavia i.e. in areas where whole grains are regularly consumed.Conclusions: Whole-grain intake, assessed by alkylresorcinols,was associated with a lower incidence of distal coloncancer. Alkylresorcinols seem useful as objective biomarkersof whole-grain intake in populations where whole-grains are astaple part of the diet. Acknowledgements: This work was supportedby World Cancer Research Fund International (WCRF)and WCRF Netherlands (WCRF NL) (2011/436), and NordForsk(Centre of Excellence programme HELGA (070015)).

  • 17. Kyro, Cecilie
    et al.
    Olsen, Anja
    Bueno-de-Mesquita, H. B(as).
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Naska, Androniki
    Oikonomidou, Despoina
    Masala, Giovanna
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Peeters, Petra H.
    Bakken, Toril
    Weiderpass, Elisabete
    Asli, Lene Angell
    Sanchez, Soledad
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Slimani, Nadia
    Freisling, Heinz
    Ferrari, Pietro
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Elio
    Tjonneland, Anne
    Landberg, Rikard
    Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2014In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 111, no 10, p. 1881-1890Article in journal (Refereed)
    Abstract [en]

    Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.

  • 18. Kyro, Cecilie
    et al.
    Olsen, Anja
    Landberg, Rikard
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Trichopoulos, Dimitrios
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H.
    Weiderpass, Elisabete
    Bakken, Toril
    Asli, Lene Angell
    Argueelles, Marcial
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Huerta, Jose Maria
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Ferrari, Pietro
    Freisling, Heinz
    Jenab, Mazda
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Eilo
    Tjonneland, Anne
    Bueno-de-Mesquita, H. B(as)
    Plasma Alkylresorcinols, Biomarkers of Whole-Grain Wheat and Rye Intake, and Incidence of Colorectal Cancer2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 1, p. djt352-Article in journal (Refereed)
    Abstract [en]

    Background Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations. Methods The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored. Results High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher). Conclusions High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.

  • 19.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Radiation Sciences. Umeå University, Faculty of Medicine, Medical Biosciences.
    Studies of LRIG1 and the ERBB receptor family in breast and colorectal cancer2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The LRIG1 gene (leucine-rich repeats and immunoglobulin like domains-1) at chromosome 3p14 is a proposed tumour suppressor gene whose gene product negatively regulates various receptor tyrosine kinases. This function has been the basis for classifying LRIG1 as a potential tumour suppressor gene (TSG). The ERBB receptor family is important in malignant cellular functions such as proliferation, survival, adhesion, migration and differentiation. In breast cancer, amplification of the ERBB2 proto-oncogene is an important negative prognostic factor. The epidermal growth factor receptor (EGFR/ERBB1), is expressed in colorectal cancer and has been correlated to a worse prognosis. Until recently, immunohistochemical analysis of EGFR expression was used to select patients suitable for treatment with EGFR targeted antibodies.

    This thesis characterizes LRIG1 in breast and colorectal cancer to gain further knowledge of the gene and its expression. Also, the EGFR expression in metastases and the invasive margin of colorectal cancers was investigated to correlate changes to clinical factors. Breast cancer samples and matched normal tissues were evaluated for LRIG1 and the ERBB receptors at gene, RNA and protein levels. An increase in copy number of the LRIG1 gene was evident. Also, increased LRIG1 copy number was associated with high levels of ERBB2 mRNA. Another set of breast cancer tumours were analysed for LRIG1 by FISH analysis. The results were coherent with the previous results. To further analyze the correlation to ERBB2, tumours with LRIG1 increased copy number were analysed for ERBB2. The data showed that 89% of tumours with increased LRIG1 copy number were either ERBB2 amplified or had an increased copy number of ERBB2.

    To investigate LRIG1 and the EGFR in colorectal cancer, the gene and protein expression was analysed by several methods in tumours and corresponding normal tissues. There were no significant changes at gene level found, but at the protein level, both over- and under expression were seen. No evident correlation between LRIG1 and EGFR expression was detected.

    The ERBB receptor family expression in colorectal cancer tumours and corresponding metastases was investigated to explore if the expression was altered in the metastatic lesion. The results showed that the EGFR expression was lost in the corresponding metastases in 33% of the tumours and that the same percentage of tumours gained expression in the metastases. Co-expression of the ERBB family members was also analysed; there was a significant increase of ERBB3/ERBB4 co-expression in late stage tumours. EGFR expression at the invasive margin of colorectal cancers was analysed to clarify whether expression correlated to the patient’s prognosis. Significant correlation to survival and the presence of budding was seen.

    In conclusion, 34% of the breast cancer tumours studied had an increased copy number of LRIG1 with a significant co-incidental increase in ERBB2 copy number. This raises the question of a functional correlation between LRIG1 and ERBB2, a finding that might be of clinical importance. The studies of EGFR and the ERBB receptors in colorectal cancer reflect the heterogeneity of EGFR expression in tumours. In addition, these findings suggest that survival of the patients correlates to an increasing EGFR expression at the invasive margin.

  • 20.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Co-incidental increase in gene copy number of ERBB2 and LRIG1 in breast cancer2009In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 11, no 3, p. 403-Article in journal (Refereed)
  • 21.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Thomasson, Marcus
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Medical Biosciences, Clinical chemistry.
    Höckenström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Emdin, Stefan
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Jonsson, Yvonne
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Increased copy number at 3p14 in breast cancer2005In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 7, no 5, p. R719-R727Article in journal (Refereed)
  • 22.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Isaksson-Mettävainio, Martin
    Öberg, Åke
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 5, p. 1489-1494Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: EGFR (epidermal growth factor receptor) targeted therapies are important new tools in colorectal cancer treatment. EGFR analysis of the primary tumour was previously recommended to identify patients who will benefit from the EGFR targeted therapy. Previous studies have displayed diverging results regarding the expression of EGFR in the primary tumour compared to the metastases. The present study was performed to investigate whether EGFR and ErbB2-4 expression differed between 64 primary tumours and their corresponding metastases.

    PATIENTS AND METHODS: EGFR and ErbB2-4 expression were analysed in the primary tumour and in the corresponding metastases using immunohistochemistry (IHC).

    RESULTS: In 49/64 samples (76%), the primary tumours were EGFR positive; in 33% (16/49) of EGFR positive samples, the tumours lost the EGFR expression in the metastasis compared to the primary tumour. From the primary tumours, 15/64 (23%) were negative and 5 of these (33%) developed EGFR expression in the metastasis. ErbB2, ErbB3, and ErbB4 expression was evident in 54%, 67%, and 81%, respectively. There was no significant difference between ErbB2, ErbB3, and ErbB4 expression in primary tumours and metastases. The co-expression of the ErbB family members was also analysed, with a significant increase of ErbB3/ErbB4 co-expression in late stage tumours.

    CONCLUSION: The EGFR expression was lost in 33% of metastasising primary colorectal cancer tumours, a finding that agrees with at least one previous study. Thus, the present results clearly implicate the need for EGFR analysis of both the primary tumour and metastases to accurately determine EGFR status when considering the use of EGFR targeted therapies.

  • 23.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Öberg, Åke
    Henriksson, Maria
    Palmqvist, Richard
    Increased EGFR expression at the invasive margin is a negative prognostic factor in colorectal cancerManuscript (preprint) (Other academic)
  • 24.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 9, p. 2031-2037Article in journal (Refereed)
    Abstract [en]

    The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFR(i)) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFR(i) group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFR(i) tumours (HR, 1.53; 95% CI, 1.04-2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.

  • 25.
    Lundberg, Ida
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    MicroRNA expression in KRAS- and BRAF-mutated colorectal cancers2018In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 38, no 2, p. 677-683Article in journal (Refereed)
    Abstract [en]

    Background/Aim: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS-and BRAF-mutated CRCs.

    Materials and Methods: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF.

    Results: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors.

    Conclusion: Our results suggest that KRAS and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS-and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.

  • 26. Nimptsch, Katharina
    et al.
    Aleksandrova, Krasimira
    Boeing, Heiner
    Janke, Juergen
    Lee, Young-Ae
    Jenab, Mazda
    Kong, So Yeon
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Bueno-de-Mesquita, H. B(As)
    Siersema, Peter D.
    Jansen, Eugene H. J. M.
    Trichopoulou, Antonia
    Tjonneland, Anne
    Olsen, Anja
    Wu, Chunsen
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Freisling, Heinz
    Katzke, Verena
    Kaaks, Rudolf
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Severi, Gianluca
    Naccarati, Alessio
    Mattiello, Amalia
    Palli, Domenico
    Grioni, Sara
    Tumino, Rosario
    Peeters, Petra H.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Brandstedt, Jenny
    Sanchez, Maria-Jose
    Gurrea, Aurelio Barricarte
    Bonet, Catalina Bonet
    Chirlaque, Maria-Dolores
    Dorronsoro, Miren
    Quiros, Jose Ramon
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nick
    Riboli, Elio
    Gunter, Marc J.
    Pischon, Tobias
    Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 4, p. 911-920Article in journal (Refereed)
    Abstract [en]

    Fetuin-A, also referred to as alpha 2-Heremans-Schmid glycoprotein (AHSG), is a liver protein known to inhibit insulin actions. Hyperinsulinemia is a possible risk factor for colorectal cancer; however, the role of fetuin-A in the development of colorectal cancer is unclear. We investigated the association between circulating fetuin-A and colorectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Fetuin-A concentrations were measured in prediagnostic plasma samples from 1,367 colorectal cancer cases and 1,367 matched controls. In conditional logistic regression models adjusted for potential confounders, the estimated relative risk (95% confidence interval) of colorectal cancer per 40 mg/mL higher fetuin-A concentrations (approximately one standard deviation) was 1.13 (1.02-1.24) overall, 1.21 (1.05-1.39) in men, 1.06 (0.93-1.22) in women, 1.13 (1.00-1.27) for colon cancer and 1.12 (0.94-1.32) for rectal cancer. To improve causal inference in a Mendelian Randomization approach, five tagging single nucleotide polymorphisms of the AHSG gene were genotyped in a subset of 456 case-control pairs. The AHSG allele-score explained 21% of the interindividual variation in plasma fetuin-A concentrations. In instrumental variable analysis, genetically raised fetuin-A was not associated with colorectal cancer risk (relative risk per 40 mg/mL genetically determined higher fetuin-A was 0.98, 95% confidence interval: 0.73-1.33). The findings of our study indicate a modest linear association between fetuin-A concentrations and risk of colorectal cancer but suggest that fetuin-A may not be causally related to colorectal cancer development.

  • 27.
    Olofsson, Roger
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Dept Surg, S-41345 Gothenburg, Sweden.
    Ny, Lars
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Dept Oncol, S-41345 Gothenburg, Sweden.
    All-Ericsson, Charlotta
    St. Erik Eye Hospital, Karolinska Institutet, Stockholm, Sweden.
    Sternby Eilard, Malin Sternby
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Tranplant Inst, S-41345 Gothenburg, Sweden.
    Rizell, Magnus
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Tranplant Inst, S-41345 Gothenburg, Sweden.
    Cahlin, Christian
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Tranplant Inst, S-41345 Gothenburg, Sweden.
    Stierner, Ulrika
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Dept Oncol, S-41345 Gothenburg, Sweden.
    Lönn, Ulf
    Linköping Univ Hosp, Dept Oncol, S-58185 Linköping, Sweden.
    Hansson, Johan
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Lundgren, Lotta
    Skåne Univ Hosp, Dept Oncol, S-22185 Lund, Sweden.
    Ullenhag, Gustav
    Uppsala Univ, Dept Radiol Oncol & Radiat Sci, Sect Oncol, S-75105 Uppsala, Sweden.
    Kiilgaard, Jens Folke
    Univ Copenhagen, Glostrup Hosp, Dept Ophthalmol, DK-2600 Glostrup, Denmark.
    Nilsson, Jonas
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Sahlgrenska Canc Ctr, S-40530 Gothenburg, Sweden.
    Lindnér, Per
    Univ Gothenburg, Sahlgrenska Univ Hosp, Sahlgrenska Acad, Inst Clin Sci,Tranplant Inst, S-41345 Gothenburg, Sweden.
    Isolated hepatic perfusion as a treatment for uveal melanoma liver metastases (the SCANDIUM trial): study protocol for a randomized controlled trial2014In: Trials, ISSN 1745-6215, E-ISSN 1745-6215, Vol. 15, p. 317-Article in journal (Refereed)
    Abstract [en]

    Background: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 50% of patients, with the liver being the most common site for metastases. The median survival for patients with liver metastases is between 6 and 12 months, and no treatment has in randomized trials ever been shown to prolong survival. A previous phase II trial using isolated hepatic perfusion (IHP) has suggested a 14-month increase in overall survival compared with a historic control group consisting of the longest surviving patients in Sweden during the same time period (26 versus 12 months). Methods/Design: This is the protocol for a multicenter phase III trial randomizing patients with isolated liver metastases of uveal melanoma to IHP or best alternative care (BAC). Inclusion criteria include liver metastases (verified by biopsy) and no evidence of extra-hepatic tumor manifestations by positron emission tomography-computed tomography (PET-CT). The primary endpoint is overall survival at 24 months, with secondary endpoints including response rate, progression-free survival, and quality of life. The planned sample size is 78 patients throughout five years. Discussion: Patients with isolated liver metastases of uveal melanoma origin have a short expected survival and no standard treatment option exists. This is the first randomized clinical trial to evaluate IHP as a treatment option with overall survival being the primary endpoint.

  • 28.
    Rutegård, Miriam
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Båtsman, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Brynolfsson, Patrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Brännström, Fredrik
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomqvist, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study2019In: Cancer Imaging, ISSN 1740-5025, E-ISSN 1470-7330, Vol. 19, article id 52Article in journal (Refereed)
    Abstract [en]

    PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882.

  • 29.
    Sjödin, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Mammaglobin and lipophilin B expression in breast tumors and their lack of effect on breast cancer cell proliferation.2008In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 28, no 3A, p. 1493-1498Article in journal (Refereed)
    Abstract [en]

    Mammaglobin (SCGB2A2) and lipophilin B (SCGB1D2) are members of the secretoglobin polypeptide family. Mammaglobin has been shown to be overexpressed in breast tumor tissue, indicating that mammaglobin might confer a growth advantage to mammaglobin-expressing tumor cells. Materials and Methods: The mammaglobin and lipophilin B mRNA expression levels were investigated in seven breast tumors and matched non-neoplastic tissues from the same patients using quantitative real-time RT-PCR. The effect of mammaglobin and lipophilin B expression on breast cancer cell proliferation rates was investigated by analyzing retrovirally transduced Hs578T cell clones. Cell proliferation rates were determined during the exponential growth phase by analyzing the change in lactate dehydrogenase activity over time. Results: All analyzed breast cancer tumors had lower expression levels of mammaglobin and lipophilin B than the respective mean level of the non-neoplastic breast tissues; no prominent overexpression was evident. There was high variability in the expression of mammaglobin and lipophilin B among the non-neoplastic samples, showing that caution should be taken when evaluating their over- and underexpression in tumors. The expression levels of mammaglobin and lipophilin B correlated with each other in the analyzed samples (p=0.001). Ectopic overexpression of mammaglobin and lipophilin B did not affect the cell proliferation rate of Hs578T breast carcinoma cells in vitro. Conclusion: Our findings suggest that the overexpression of mammaglobin observed in certain breast tumors is an epiphenomenon not causally involved in breast carcinogenesis.

  • 30. Thompson, Patricia A.
    et al.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Tsavachidis, Spyros
    Brewster, Abenaa
    Sahin, Aysegul
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Loss of LRIG1 Locus Increases Risk of Early and Late Relapse of Stage I/II Breast Cancer2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 11, p. 2928-2935Article in journal (Refereed)
    Abstract [en]

    Gains and losses at chromosome 3p12-21 are common in breast tumors and associated with patient outcomes. We hypothesized that the LRIG1 gene at 3p14.1, whose product functions in ErbB-family member degradation, is a critical tumor modifier at this locus. We analyzed 971 stage I/II breast tumors using Affymetrix Oncoscan molecular inversion probe arrays that include 12 probes located within LRIG1. Copy number results were validated against gene expression data available in the public database. By partitioning the LRIG1 probes nearest exon 12/13, we confirm a breakpoint in the gene and show that gains and losses in the subregions differ by tumor and patient characteristics including race/ethnicity. In analyses adjusted for known prognostic factors, loss of LRIG1 was independently associated with risk of any relapse (HR, 1.90; 95% CI, 1.32-2.73), relapse >= 5 years (HR, 2.39; 95% CI, 1.31-4.36), and death (HR, 1.55; 95% CI, 1.11-2.16). Analyses of copy number across chromosome 3, as well as expression data from pooled, publicly available datasets, corroborated the hypothesis of an elevated and persistent risk among cases with loss of or low LRIG1. We concluded that loss/low expression of LRIG1 is an independent risk factor for breast cancer metastasis and death in stage I/II patients. Increased hazard in patients with loss/low LRIG1 persists years after diagnosis, suggesting that LRIG1 is acting as a critical suppressor of tumor metastasis and is an early clinical indicator of risk for late recurrences in otherwise low-risk patients.

  • 31.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Plasma miRNA can detect colorectal cancer, but how early?2018In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 7, no 5, p. 1697-1705Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is a major cause of deaths worldwide but has a good prognosis if detected early. The need for efficient, preferable non‐ or minimally invasive, inexpensive screening tools is therefore critical. We analyzed 12 miRNAs in pre‐ and postdiagnostic plasma samples to evaluate their potential as CRC screening markers. We used a unique study design with two overlapping cohorts, allowing analysis of pre‐ and postdiagnostic samples from 58 patients with CRC and matched healthy controls. Plasma concentrations of miR‐15b, ‐16, ‐18a, ‐19a, 21, ‐22, ‐25, ‐26a, ‐29c, ‐142‐5p, ‐150, and ‐192 were measured by semi‐quantitative real‐time PCR. Concentrations of miR‐18a, ‐21, ‐22, and ‐25 in plasma from patients with CRC were significantly altered compared to healthy controls. Combined as a multimarker panel, they detected CRC with an AUC of 0.93. Furthermore, levels of these three miRNAs also showed different levels in the prediagnostic case samples close to diagnosis. Only miR‐21‐levels were elevated several years before diagnosis. Plasma levels of miR‐18a, ‐21, ‐22, and ‐25 show promise as screening biomarkers for CRC. However, based on our unique analysis of prediagnostic and postdiagnostic samples from the same patients, we conclude that circulating miRNAs elevated at diagnosis may not automatically be suitable for CRC screening, if the increase occurs too close to clinical diagnosis.

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