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  • 1. Abrahamsson, Jonas
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jónsson, Olafur G
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Hasle, Henrik
    Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate2011Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 29, nr 3, s. 310-315Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The NOPHO-AML 2004 induction strategy gives an excellent remission rate with low toxic mortality in an unselected population. Outcome is worse in patients with intermediate response but may be improved by intensifying consolidation in this group using SCT.

  • 2. Andersen, Mette K.
    et al.
    Autio, Kirsi
    Barbany, Gisela
    Borgstroem, Georg
    Cavelier, Lucia
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H.
    Johansson, Bertil
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Paediatric B-cell precursor acute lymphoblastic leukaemia with t(1;19)(q23;p13): clinical and cytogenetic characteristics of 47 cases from the Nordic countries treated according to NOPHO protocols2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 155, nr 2, s. 235-243Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The translocation t(1;19)(q23;p13)/der(19) t(1;19) is a risk stratifying aberration in childhood B-cell precursor acute lymphoblastic leukaemia (BCP ALL) in the Nordic countries. We have identified 47 children/adolescents with t(1;19)/der(19) t(1;19)-positive BCP ALL treated on two successive Nordic Society of Paediatric Haematology and Oncology (NOPHO) protocols between 1992 and 2007 and have reviewed the clinical and cytogenetic characteristics of these cases, comprising 1.8% of all cases. The translocation was balanced in 15 cases (32%) and unbalanced in 29 cases (62%). The most common additional chromosome abnormalities were del(9p), i(9q), del(6q), and del(13q). The median age was 7 years, the median white blood cell (WBC) count was 16 x 10(9)/l, and the female/male ratio was 1.2. The predicted event-free survival (EFS) at 5 and 10 years was 0.79, whereas the predicted overall survival (OS) at 5 and 10 years was 0.85 and 0.82, respectively. Nine patients had a bone marrow relapse after a median of 23 months; no patient had a central nervous system relapse. Additional cytogenetic abnormalities, age, gender, WBC count or whether the t(1;19) was balanced or unbalanced did not influence EFS or OS. Compared to cases with t(12,21) and high hyperdiploidy, EFS was similar, but overall survival was worse in patients with t(1;19)/der(19) t(1;19) (P = 0.004).

  • 3. Balgobind, Brian V
    et al.
    Raimondi, Susana C
    Harbott, Jochen
    Zimmermann, Martin
    Alonzo, Todd A
    Auvrignon, Anne
    Beverloo, H Berna
    Chang, Myron
    Creutzig, Ursula
    Dworzak, Michael N
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gibson, Brenda
    Hasle, Henrik
    Harrison, Christine J
    Heerema, Nyla A
    Kaspers, Gertjan J L
    Leszl, Anna
    Litvinko, Nathalia
    Nigro, Luca Lo
    Morimoto, Akira
    Perot, Christine
    Pieters, Rob
    Reinhardt, Dirk
    Rubnitz, Jeffrey E
    Smith, Franklin O
    Stary, Jan
    Stasevich, Irina
    Strehl, Sabine
    Taga, Takashi
    Tomizawa, Daisuke
    Webb, David
    Zemanova, Zuzana
    Zwaan, C Michel
    van den Heuvel-Eibrink, Marry M
    Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study.2009Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 114, nr 12, s. 2489-2496Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.

  • 4. Barbany, Gisela
    et al.
    Andersen, Mette K
    Autio, Kirsti
    Borgström, Georg
    Franco, Lucia Cavalier
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johansson, Bertil
    Johannsson, Johann H
    Kjeldsen, Eigil
    Nordgren, Ann
    Palmqvist, Lars
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Additional aberrations of the ETV6 and RUNX1 genes have no prognostic impact in 229 t(12;21)(p13;q22)-positive B-cell precursor acute lymphoblastic leukaemias treated according to the NOPHO-ALL-2000 protocol2012Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 36, nr 7, s. 936-938Artikel i tidskrift (Refereegranskat)
  • 5. Berglund, Eva C.
    et al.
    Lindqvist, Carl Mårten
    Hayat, Shahina
    Övernäs, Elin
    Henriksson, Niklas
    Nordlund, Jessica
    Wahlberg, Per
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lönnerholm, Gudmar
    Syvänen, Ann-Christine
    Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment2013Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, s. 856-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing. Results: We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792-1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools. Conclusion: Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.

  • 6. Björklund, Elisabet
    et al.
    Matinlauri, Irma
    Tierens, Anne
    Axelsson, Susanne
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jacobsson, Stefan
    Ahlberg, Asa Jeppsson
    Kauric, Goran
    Mäntymaa, Pentti
    Osnes, Liv
    Penttilä, Tarja-Leena
    Marquart, Hanne
    Savolainen, Eeva-Riitta
    Siitonen, Sanna
    Torikka, Kerstin
    Mazur, Joanna
    Porwit, Anna
    Quality control of flow cytometry data analysis for evaluation of minimal residual disease in bone marrow from acute leukemia patients during treatment.2009Ingår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 31, nr 6, s. 406-415Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low levels of leukemia cells in the bone marrow, minimal residual disease (MRD), are considered to be a powerful indicator of treatment response in acute lymphatic leukemia (ALL). A Nordic quality assurance program, aimed on standardization of the flow cytometry MRD analysis, has been established before implementation of MRD at cutoff level 10 as one of stratifying parameters in next Nordic Society of Pediatric Hematology and Oncology (NOPHO) treatment program for ALL. In 4 quality control (QC) rounds 15 laboratories determined the MRD levels in 48 follow-up samples from 12 ALL patients treated according to NOPHO 2000. Analysis procedures were standardized. For each QC round a compact disc containing data in list-mode files was sent out and results were submitted to a central laboratory. At cutoff level 10, which will be applied for clinical decisions, laboratories obtained a high concordance (91.6%). If cutoff level 10 was applied, the concordance would be lower (85.3%). The continuing standardization resulted in better concordance in QC3 and QC4 compared with QC1 and QC2. The concordance was higher in precursor B as compared with T-cell ALL. We conclude that after standardization, flow cytometry MRD detection can be reliably applied in international, multicenter treatment protocols.

  • 7. Blink, Marjolein
    et al.
    Zimmermann, Martin
    von Neuhoff, Christine
    Reinhardt, Dirk
    de Haas, Valerie
    Hasle, Henrik
    O'Brien, Maureen M
    Stark, Batia
    Tandonnet, Julie
    Pession, Andrea
    Tousovska, Katerina
    Cheuk, Daniel K L
    Kudo, Kazuko
    Taga, Takashi
    Rubnitz, Jeffrey E
    Haltrich, Iren
    Balwierz, Walentyna
    Pieters, Rob
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Johansson, Bertil
    van den Heuvel-Eibrink, Marry M
    Zwaan, C Michel
    Normal karyotype is a poor prognostic factor in myeloid leukemia of Down syndrome: a retrospective, international study2014Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, nr 2, s. 299-307Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Myeloid leukemia of Down syndrome has a better prognosis than sporadic pediatric acute myeloid leukemia. Most cases of myeloid leukemia of Down syndrome are characterized by additional cytogenetic changes besides the constitutional trisomy 21, but their potential prognostic impact is not known. We, therefore, conducted an international retrospective study of clinical characteristics, cytogenetics, treatment, and outcome of 451 children with myeloid leukemia of Down syndrome. All karyotypes were centrally reviewed before assigning patients to subgroups. The overall 7-year event-free survival for the entire cohort was 78% (± 2%), with the overall survival rate being 79% (± 2%), the cumulative incidence of relapse 12% (± 2%), and the cumulative incidence of toxic death 7% (± 1%). Outcome estimates showed large differences across the different cytogenetic subgroups. Based on the cumulative incidence of relapse, we could risk-stratify patients into two groups: cases with a normal karyotype (n=103) with a higher cumulative incidence of relapse (21%± 4%) than cases with an aberrant karyotype (n=255) with a cumulative incidence of relapse of 9% (± 2%) (P=0.004). Multivariate analyses revealed that white blood cell count ≥ 20 × 10(9)/L and age >3 years were independent predictors for poor event-free survival, while normal karyotype independently predicted inferior overall survival, event-free survival, and relapse-free survival. In conclusion, this study showed large differences in outcome within patients with myeloid leukemia of Down syndrome and identified novel prognostic groups that predicted clinical outcome and hence may be used for stratification in future treatment protocols.

  • 8.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Cullman, Inger
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011Ingår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, nr 12, s. 1144-1151Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51 61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

  • 9.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65373-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  • 10.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016Ingår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, nr 7, s. 1185-1192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

  • 11.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordlund, Jessica
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018Ingår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, artikel-id 31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

    Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

    Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

    Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

  • 12. Buitenkamp, Trudy D.
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heerema, Nyla A.
    van den Heuvel-Eibrink, Marry M.
    Pieters, Rob
    Korbijn, Carin M.
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cheng
    Horibe, Keizo
    Arico, Maurizio
    Biondi, Andrea
    Basso, Giuseppe
    Rabin, Karin R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Morak, Maria
    Panzer-Grumayer, Renate
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Ganmore, Ithamar
    Moorman, Anthony V.
    Vora, Ajay
    Hunger, Stephen P.
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy R.
    Whitlock, James A.
    Zwaan, C. Michel
    Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group2014Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, nr 1, s. 70-77Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Munster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% +/- 2% vs 15% +/- 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% +/- 1% vs 2.0% +/- < 1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% +/- 2% vs 81% +/- 2%, P < .0001) and overall survival (74% +/- 2% vs 89% +/- 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] = 0.58, P = .002), white blood cell (WBC) count <10 x 10(9)/L (HR = 0.60, P = .005), and ETV6-RUNX1 (HR = 0.14, P = .006) for EFS and age (HR = 0.48, P < .001), ETV6-RUNX1 (HR = 0.1, P = .016) and high hyperdiploidy (HeH) (HR = 0.29, P = .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DS-ALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups.

  • 13. Buitenkamp, Trudy
    et al.
    Izraeli, Shai
    Zimmermann, Martin
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heerema, Nyla A.
    van den Heuvel, Marry M.
    Pieters, Rob
    de Haas, Valerie
    Silverman, Lewis B.
    Schmiegelow, Kjeld
    Liang, Der-Cherng
    Horibe, Keizo
    Arico, Maurizio
    Cazzaniga, Giovanni
    Basso, Giuseppe
    Rabin, Karen R.
    Schrappe, Martin
    Cario, Gunnar
    Mann, Georg
    Mondelaers, Veerle
    Lammens, Tim
    Cave, Helene
    Stark, Batia
    Moorman, Anthony V.
    Vora, Ajay J.
    Hunger, Stephen
    Pui, Ching-Hon
    Mullighan, Charles G.
    Manabe, Atsushi
    Escherich, Gabriele
    Kowalczyk, Jerzy
    Whitlock, James A.
    Zwaan, Christian M.
    Acute Lymphoblastic Leukemia in children with Down Syndrome: A report from the Ponte Di Legno Study Group2011Ingår i: 53rd ASH Annual Meeting and Exposition, December 10-13, 2011: Program: Oral and Poster AbstractsSession: 612. Acute Lymphoblastic Leukemia - Biology and Pathophysiology: Poster III Monday, December 12, 2011, 6:00 PM-8:00 PM Hall GH (San Diego Convention Center), American Society of Hematology , 2011, Vol. 118, nr 21Konferensbidrag (Refereegranskat)
  • 14. Coenen, Eva A
    et al.
    Raimondi, Susana C
    Harbott, Jochen
    Zimmermann, Martin
    Alonzo, Todd A
    Auvrignon, Anne
    Beverloo, H Berna
    Chang, Myron
    Creutzig, Ursula
    Dworzak, Michael N
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gibson, Brenda
    Hasle, Henrik
    Harrison, Christine J
    Heerema, Nyla A
    Kaspers, Gertjan J L
    Leszl, Anna
    Litvinko, Nathalia
    Lo Nigro, Luca
    Morimoto, Akira
    Perot, Christine
    Reinhardt, Dirk
    Rubnitz, Jeffrey E
    Smith, Franklin O
    Stary, Jan
    Stasevich, Irina
    Strehl, Sabine
    Taga, Takashi
    Tomizawa, Daisuke
    Webb, David
    Zemanova, Zuzana
    Pieters, Rob
    Zwaan, C Michel
    van den Heuvel-Eibrink, Marry M
    Prognostic significance of additional cytogenetic aberrations in 733 de novo pediatric 11q23/MLL-rearranged AML patients: results of an international study2011Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 117, nr 26, s. 7102-7111Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We previously demonstrated that outcome of pediatric 11q23/MLL-rearranged AML depends on the translocation partner (TP). In this multicenter international study on 733 children with 11q23/MLL-rearranged AML, we further analyzed which additional cytogenetic aberrations (ACA) had prognostic significance. ACAs occurred in 344 (47%) of 733 and were associated with unfavorable outcome (5-year overall survival [OS] 47% vs 62%, P < .001). Trisomy 8, the most frequent specific ACA (n = 130/344, 38%), independently predicted favorable outcome within the ACAs group (OS 61% vs 39%, P = .003; Cox model for OS hazard ratio (HR) 0.54, P = .03), on the basis of reduced relapse rate (26% vs 49%, P < .001). Trisomy 19 (n = 37/344, 11%) independently predicted poor prognosis in ACAs cases, which was partly caused by refractory disease (remission rate 74% vs 89%, P = .04; OS 24% vs 50%, P < .001; HR 1.77, P = .01). Structural ACAs had independent adverse prognostic value for event-free survival (HR 1.36, P = .01). Complex karyotype, defined as ≥ 3 abnormalities, was present in 26% (n = 192/733) and showed worse outcome than those without complex karyotype (OS 45% vs 59%, P = .003) in univariate analysis only. In conclusion, like TP, specific ACAs have independent prognostic significance in pediatric 11q23/MLL-rearranged AML, and the mechanism underlying these prognostic differences should be studied.

  • 15. Davidsson, J
    et al.
    Paulsson, K
    Lindgren, D
    Lilljebjörn, H
    Chaplin, T
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Andersen, M K
    Nordgren, A
    Rosenquist, R
    Fioretos, T
    Young, B D
    Johansson, B
    Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations.2010Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 24, nr 5, s. 924-31Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Although childhood high hyperdiploid acute lymphoblastic leukemia is associated with a favorable outcome, 20% of patients still relapse. It is important to identify these patients already at diagnosis to ensure proper risk stratification. We have investigated 11 paired diagnostic and relapse samples with single nucleotide polymorphism array and mutation analyses of FLT3, KRAS, NRAS and PTPN11 in order to identify changes associated with relapse and to ascertain the genetic evolution patterns. Structural changes, mainly cryptic hemizygous deletions, were significantly more common at relapse (P<0.05). No single aberration was linked to relapse, but four deletions, involving IKZF1, PAX5, CDKN2A/B or AK3, were recurrent. On the basis of the genetic relationship between the paired samples, three groups were delineated: (1) identical genetic changes at diagnosis and relapse (2 of 11 cases), (2) clonal evolution with all changes at diagnosis being present at relapse (2 of 11) and (3) clonal evolution with some changes conserved, lost or gained (7 of 11), suggesting the presence of a preleukemic clone. This ancestral clone was characterized by numerical changes only, with structural changes and RTK-RAS mutations being secondary to the high hyperdiploid pattern.

  • 16.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Ingår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, s. 606-615Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 17. Fogelstrand, Linda
    et al.
    Staffas, Anna
    Wasslavik, Carina
    Sjogren, Helene
    Soderhall, Stefan
    Frost, Britt-Marie
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Behrendtz, Mikael
    Heldrup, Jesper
    Karrman, Kristina
    Johansson, Bertil
    Heyman, Mats
    Abrahamsson, Jonas
    Palmqvist, Lars
    Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols2014Ingår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, nr 3, s. 424-430Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.

    Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.

    Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.

    Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.

  • 18.
    Forestier, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gauffin, Fredrika
    Andersen, Mette K
    Autio, Kirsi
    Borgström, Georg
    Golovleva, Irina
    Gustafsson, Britt
    Heim, Sverre
    Heinonen, Kristina
    Heyman, Mats
    Hovland, Randi
    Johannsson, Johann H
    Kerndrup, Gitte
    Rosenquist, Richard
    Schoumans, Jacqueline
    Swolin, Birgitta
    Johansson, Bertil
    Nordgren, Ann
    Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature.2008Ingår i: Genes Chromosomes Cancer, ISSN 1098-2264, Vol. 47, nr 2, s. 149-58Artikel i tidskrift (Övrigt vetenskapligt)
  • 19.
    Forestier, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heyman, Mats
    Andersen, Mette K
    Autio, Kirsi
    Blennow, Elisabeth
    Borgström, Georg
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Johannsson, Johann H
    Kerndrup, Gitte
    Nordgren, Ann
    Rosenquist, Richard
    Swolin, Birgitta
    Johansson, Bertil
    Outcome of ETV6/RUNX1-positive childhood acute lymphoblastic leukaemia in the NOPHO-ALL-1992 protocol: frequent late relapses but good overall survival.2008Ingår i: Br J Haematol, ISSN 1365-2141, Vol. 140, nr 6, s. 665-72Artikel i tidskrift (Övrigt vetenskapligt)
  • 20.
    Forestier, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Izraeli, Shai
    Beverloo, Berna
    Haas, Oskar
    Pession, Andrea
    Michalova, Kyra
    Stark, Batia
    Harrison, Christine J
    Teigler-Schlegel, Andrea
    Johansson, Bertil
    Cytogenetic features of acute lymphoblastic and myeloid leukemias in pediatric patients with Down syndrome - an iBFM-SG study.2007Ingår i: Blood, ISSN 0006-4971Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Children with Down syndrome (DS) have a markedly increased risk of acute lymphoblastic and myeloid leukemias (ALL+AML). To identify chromosomal changes cooperating with +21 that may provide information on the pathogenesis of these leukemias, we analyzed 215 DS-ALL and 189 DS-AML. Unlike previous smaller series, a significant proportion of DS-ALL had the typical B-cell precursor ALL abnormalities high hyperdiploidy (HeH; 11%) and t(12;21)(p13;q22) (10%). The HeH DS-ALL were characterized by gains of the same chromosomes as non-DS-HeH, suggesting the same etiology/pathogenesis. In addition, specific genetic subtypes of DS-ALL were suggested by the significant overrepresentation of cases with +X, t(8;14)(q11;q32), and del(9p). Unlike DS-ALL, the common translocations associated with non-DS-AML were rare in DS-AML, which instead were characterized by the frequent presence of dup(1q), del(6q), del(7p), dup(7q), +8, +11, del(16q), and +21. This series of DS leukemias - the largest to date - reveals that DS-ALL is a heterogeneous disorder that comprises both t(12;21) and HeH as well as DS-related abnormalities. Furthermore, this analysis confirms that DS-AML is a distinct entity, originating through other genetic pathways than do non-DS-AML, and suggests that unbalanced changes such as dup(1q), +8, and +21 are involved in the leukemogenic process.

  • 21.
    Forestier, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schmiegelow, Kjeld
    The incidence peaks of the childhood acute leukemias reflect specific cytogenetic aberrations.2006Ingår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 28, nr 8, s. 486-95Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The correlation between age and karyotype was studied in 1425, 0 to 14.9 years old children who were diagnosed with acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia. Almost 80% of the non-Down B-cell precursor ALL cases in the 2 to 7 years frequency peak group who had aberrant cytogenetic results had either a high-hyperdiploid clone (51 to 61 chromosomes) or a translocation t(12;21)(p13;q22). Among B-cell precursor ALL cases, high white blood cell counts correlated with earlier age at diagnosis (rS=-0.23; P<0.001) being most evident for 11q23/MLL-aberrations, translocation t(12;21)(p13;q22), and high-hyperdiploidy. Among acute myeloblastic leukemia patients, frequency peaks were found for those with MLL/11q23 rearrangements (peak: first year), Down syndrome (peak: second to third year), or cytogenetic abnormalities other than translocations t(8;21), t(15;17), and inv(16)/t(16;16) (peak: first to third year). The epidemiology of the cytogenetic subsets of acute leukemias questions whether age as a disease-related prognostic parameter has any relevance in childhood leukemia clinical research beyond being a surrogate marker for more important, truly biologic features such as cytogenetic aberrations and white cell count at diagnosis. Further research is needed to explore whether the 2 to 7 years age incidence peak in childhood ALL harbor yet unidentified cytogenetic subsets with the same natural history as the high-hyperdiploid and t(12;21)-positive leukemias.

  • 22. Frost, B M
    et al.
    Forestier, E
    Gustafsson, G
    Nygren, P
    Hellebostad, M
    Jonmundsson, G
    Kanerva, J
    Schmiegelow, K
    Larsson, R
    Lönnerholm, G
    Translocation t(1;19) is related to low cellular drug resistance in childhood acute lymphoblastic leukaemia.2005Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 19, nr 1, s. 165-9Artikel i tidskrift (Refereegranskat)
  • 23. Frost, Britt-Marie
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gustafsson, Göran
    Nygren, Peter
    Hellebostad, Marit
    Jonsson, Olafur G
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Larsson, Rolf
    Lönnerholm, Gudmar
    Translocation t(12;21) is related to in vitro cellular drug sensitivity to doxorubicin and etoposide in childhood acute lymphoblastic leukemia2004Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 104, nr 8, s. 2452-2457Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The t(12;21) (p13;q22) translocation resulting in ETV6/RUNX1 (previously named TEL/AML1) gene fusion is present in about 25% of children with precursor B-lineage acute lymphoblastic leukemia (B-ALL). We successfully tested 275 precursor BALL samples from children aged 1 to 17 years to determine the relation between t(12;21) and in vitro cellular drug resistance, measured by the fluorometric microculture cytotoxicity assay (FMCA). Samples from 83 patients (30%) were positive for t(12;21). The ETV6/RUNX1(+) samples were significantly more sensitive than ETV6/RUNX1(-) samples to doxorubicin, etoposide, amsacrine, and dexamethasone, whereas the opposite was true for cytarabine. After matching for unevenly distributed patient characteristics, that is, excluding patients with high hyperdiploidy (> 51 chromosomes), t(g;22), t(1;19), or 11q23 rearrangement, the ETV6/RUNX1(+) samples remained significantly more sensitive to doxorubicin (P = .001) and etoposide (P = .001). For the other drugs tested (amsacrine, cytarabine, dexamethasone, prednisolone, vincristine, 6-thioguanine, and 4-hydroper-oxy-cyclophosphamide), no significant difference in cellular drug sensitivity was found. In conclusion, we found that the presence of the t(12;21) translocation in childhood precursor B-ALL is associated with a high tumor cell sensitivity to doxorubicin and etoposide. High throughput techniques should now be used to elucidate the cellular mechanisms by which ETV6/RUNX1 gene fusion is linked to increased sensitivity to these drugs.

  • 24. Gustafsson, Britt
    et al.
    Honkaniemi, Emma
    Goh, Shan
    Giraud, Geraldine
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    von Dobeln, Ulrika
    Allander, Tobias
    Dalianis, Tina
    Bogdanovic, Gordana
    KI, WU, and Merkel Cell Polyomavirus DNA was not Detected in Guthrie Cards of Children who Later Developed Acute Lymphoblastic Leukemia2012Ingår i: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 34, nr 5, s. 364-367Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Neonatal dried blood spots (Guthrie cards) have been used to demonstrate a prenatal origin of clonal leukemia-specific genetic aberrations in several subgroups of childhood acute lymphoblastic leukemia (ALL). One hypothesis suggests that an infectious agent could initiate genetic transformation already in utero. In search for a possible viral agent, Guthrie cards were analyzed for the presence of 3 newly discovered polyomavirus Karolinska Institutet polymavirus (KIPyV), Washington University polyomavirus (WUPyV), and Merkel cell polyomavirus (MCPyV). Methods: Guthrie cards from 50 children who later developed ALL and 100 matched controls were collected and analyzed by standard or real-time polymerase chain reaction for the presence of the VP1 region of KIPyV, WUPyV, and MCPyV, and the LT region for MCPyV. Results and Conclusions: DNA from KIPyV, WUPyV, and MCPyV was not detected in neonatal blood samples from children with ALL or controls. Prenatal infections with these viruses are not likely to be etiological drivers for childhood leukemogenesis.

  • 25. Harrison, C. J.
    et al.
    Moorman, A. V.
    Schwab, C.
    Carroll, A. J.
    Raetz, E. A.
    Devidas, M.
    Strehl, S.
    Nebral, K.
    Harbott, J.
    Teigler-Schlegel, A.
    Zimmerman, M.
    Dastuge, N.
    Baruchel, A.
    Soulier, J.
    Auclerc, M-F
    Attarbaschi, A.
    Mann, G.
    Stark, B.
    Cazzaniga, G.
    Chilton, L.
    Vandenberghe, P.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Haltrich, I.
    Raimondi, S. C.
    Parihar, M.
    Bourquin, J-P
    Tchinda, J.
    Haferlach, C.
    Vora, A.
    Hunger, S. P.
    Heerema, N. A.
    Haas, O. A.
    An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome2014Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, nr 5, s. 1015-1021Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.

  • 26. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    De Bont, Evelina S.
    de Haas, Valerie
    De Moerloose, Barbara
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Ha, Shau Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Reedijk, Ardine
    Saks, Kadri
    Zeller, Bernward
    Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML2014Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikel i tidskrift (Övrigt vetenskapligt)
  • 27. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab Ozogamicin as Post-Consolidation Therapy does not prevent relapse in children with AML: Results of the NOPHO-AML 2094 Study2011Ingår i: 53rd ASH Annual Meeting and Exposition, December 10-13, 2011 : Program: Oral and Poster AbstractsSession: 615. Acute Myeloid Leukemia - Therapy, excluding Transplantation: Poster I Saturday, December 10, 2011, 5:30 PM-7:30 PM Hall GH (San Diego Convention Center), 2011, Vol. 118, nr 21, s. 667-667Konferensbidrag (Refereegranskat)
  • 28. Hasle, Henrik
    et al.
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jonsson, Olafur Gisli
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML: results from NOPHO-AML 20042012Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 5, s. 978-984Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m(2) and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5):978-984)

  • 29. Hjalgrim, Lisa Lyngsie
    et al.
    Rostgaard, Klaus
    Hjalgrim, Henrik
    Westergaard, Tine
    Thomassen, Harald
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Gustafsson, Göran
    Kristinsson, Jon
    Melbye, Mads
    Schmiegelow, Kjeld
    Birth weight and risk for childhood leukemia in Denmark, Sweden, Norway, and Iceland2004Ingår i: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 96, nr 20, s. 1549-1556Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Compelling evidence suggests that childhood leukemia often originates in utero. Birth weight is one of the few pregnancy-related risk factors that has been associated with leukemia risk, but the association has remained poorly characterized. We conducted a population-based case-control stud-v in Denmark, Sweden, Norway, and Iceland to investigate the association between birth weight (and other birth characteristics) and the risk of childhood leukemia.

    Methods: Overall, 1905 children (aged 0-14 years) with acute lymphoblastic leukemia (ALL) and 299 children with acute myeloid leukemia (AML) diagnosed between January 1, 1984, and December 31, 1999, were identified in the Nordic Society of Paediatric Haematology and Oncology acute leukemia database. Each case patient was matched to five population control subjects (n = 1.0 745) on nationality, age, and sex. All live-born siblings of case patients (n = 3812) and control subjects (n = 17 937) were also identified in population registers. Information on birth weight and gestational age at birth was ascertained from the national Medical Birth Registers. The association between various birth characteristics and leukemia risk was assessed by conditional logistic regression. All statistical tests were two-sided.

    Results: Risk of ALL overall was statistically significantly associated with birth weight (odds ratio [OR] = 1.26 per 1-kg increase in birth weight, 95% confidence interval [CI] = 1.13 to 1.41). The association was similar for B- and T-lineage ALL and across all diagnostic ages (0-14 years). However, children with ALL did not weigh more at birth than their siblings. Statistically significantly reduced risks of B-precursor ALL were observed with increasing position in the birth order (OR = 0.90 per position increase, 95% CI = 0.84 to 0.96) and increasing gestational age (OR = 0.87 per 2-week increase in gestational age, 95% CI = 0.81 to 0.94). Risk of AML did not vary monotonically with birth weight, and low birth weight (<1500 g [i.e., 3.3 pounds]) was associated with the highest risk.

    Conclusion: Our results are compatible with the hypothesis that a high birth weight is associated with an increased risk of ALL.

  • 30. Honkaniemi, E
    et al.
    Talekar, G
    Huang, W
    Bogdanovic, G
    Forestier, E
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    von Doblen, U
    Engvall, M
    Ornelles, D A
    Gooding, L R
    Gustafsson, B
    Adenovirus DNA in Guthrie cards from children who develop acute lymphoblastic leukaemia (ALL).2010Ingår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 102, nr 5, s. 796-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: In search of a proposed viral aetiology of childhood acute lymphoblastic leukaemia (ALL), the common species C adenoviruses were analysed in Guthrie cards. METHODS: Guthrie cards from 243 children who later developed ALL and from 486 matched controls were collected and analysed by nested polymerase chain reaction for the presence of adenovirus DNA. RESULTS: Adenovirus DNA was reliably detected from only two subjects, both of whom developed ALL. CONCLUSION: Adenovirus DNA is detected in Guthrie card samples at too low a frequency to reveal an association between adenovirus and the development of leukaemia.

  • 31. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dastugue, Nicole
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå University Hospital, Umea, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Pediatric Acute Megakaryoblastic Leukemia without Down Syndrome: A Retrospective Study by the International Berlin-Frankfurt-Munster Study Group (I-BFMSG)2014Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikel i tidskrift (Övrigt vetenskapligt)
  • 32. Inaba, Hiroto
    et al.
    Zhou, Yinmei
    Abla, Oussama
    Adachi, Souichi
    Auvrignon, Anne
    Beverloo, H. Berna
    de Bont, Eveline
    Chang, Tai-Tsung
    Creutzig, Ursula
    Dworzak, Michael
    Elitzur, Sarah
    Fynn, Alcira
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Nordic Society for Pediatric Hematology and Oncology, Stockholm, Sweden.
    Hasle, Henrik
    Liang, Der-Cherng
    Lee, Vincent
    Locatelli, Franco
    Masetti, Riccardo
    De Moerloose, Barbara
    Reinhardt, Dirk
    Rodriguez, Laura
    Van Roy, Nadine
    Shen, Shuhong
    Taga, Takashi
    Tomizawa, Daisuke
    Yeoh, Allen E. J.
    Zimmermann, Martin
    Raimondi, Susana C.
    Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study2015Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 13, s. 1575-1584Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Comprehensive clinical studies of patients with acute megakaryoblastic leukemia (AMKL) are lacking. We performed an international retrospective study on 490 patients (age <= 18 years) with non-Down syndrome de novo AMKL diagnosed from 1989 to 2009. Patients with AMKL (median age 1.53 years) comprised 7.8% of pediatric AML. Five-year event-free (EFS) and overall survival (OS) were 43.7% +/- 2.7% and 49.0% +/- 2.7%, respectively. Patients diagnosed in 2000 to 2009 were treated with higher cytarabine doses and had better EFS (P = .037) and OS (P = .003) than those diagnosed in 1989 to 1999. Transplantation in first remission did not improve survival. Cytogenetic data were available for 372 (75.9%) patients: hypodiploid (n = 18, 4.8%), normal karyotype (n = 49, 13.2%), pseudodiploid (n = 119, 32.0%), 47 to 50 chromosomes (n = 142, 38.2%), and >50 chromosomes (n=44, 11.8%). Chromosome gain occurred in 195 of 372 (52.4%) patients: +21 (n = 106, 28.5%), +19 (n = 93, 25.0%), +8 (n = 77, 20.7%). Losses occurred in 65 patients (17.5%): -7 (n = 13, 3.5%). Common structural chromosomal aberrations were t(1; 22)(p13; q13) (n = 51, 13.7%) and 11q23 rearrangements (n = 38, 10.2%); t(9; 11)(p22; q23) occurred in 21 patients. On the basis of frequency and prognosis, AMKL can be classified to 3 risk groups: good risk-7p abnormalities; poor risk-normal karyotypes, -7, 9p abnormalities including t(9;11)(p22;q23)/MLL-MLLT3, -13/13q-, and -15; and intermediate risk-others including t(1;22)(p13;q13)/OTT-MAL (RBM15-MKL1) and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes.

  • 33. Karlsson, Lene
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Hasle, Henrik
    Jahnukainen, Kirsi
    Jonsson, Olafur G.
    Lausen, Birgitte
    Nyström, Ulrika Noren
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Palle, Josefine
    Tierens, Anne
    Zeller, Bernward
    Abrahamsson, Jonas
    Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia2017Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 178, nr 4, s. 592-602Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y) was 39 +/- 4% for the whole group and 43 +/- 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) +/- anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse >= 1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 +/- 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.

  • 34. Karlsson, Lene
    et al.
    Nyvold, Charlotte Guldborg
    Palmqvist, Lars
    Tierens, Anne
    Hasle, Henrik
    Lausen, Birgitte
    Jonsson, Olafur G.
    Juergensen, Gitte Wulff
    Ebbesen, Lene Hyldahl
    Kuchenbauer, Florian
    Forestier, Erik
    Umeå University, Sweden.
    Abrahamsson, Jonas
    Fogelstrand, Linda
    Quantification of Fusion Transcripts Reveals Slower Treatment Kinetics As Compared with Multiparameter Flow Cytometry during Induction Treatment of Acute Myeloid Leukemia in Children2018Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Artikel i tidskrift (Övrigt vetenskapligt)
  • 35. Karrman, Kristina
    et al.
    Castor, Anders
    Behrendtz, Mikael
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Olsson, Linda
    Ehinger, Mats
    Biloglav, Andrea
    Fioretos, Thoas
    Paulsson, Kajsa
    Johansson, Bertil
    Deep sequencing and SNP array analyses of pediatric T-cell acute lymphoblastic leukemia reveal NOTCH1 mutations in minor subclones and a high incidence of uniparental isodisomies affecting CDKN2A2015Ingår i: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 8, artikel-id 42Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that arises in a multistep fashion through acquisition of several genetic aberrations, subsequently giving rise to a malignant, clonal expansion of T-lymphoblasts. The aim of the present study was to identify additional as well as cooperative genetic events in T-ALL.

    Methods: A population-based pediatric T-ALL series comprising 47 cases was investigated by SNP array and deep sequencing analyses of 75 genes, in order to ascertain pathogenetically pertinent aberrations and to identify cooperative events.

    Results: The majority (92%) of cases harbored copy number aberrations/uniparental isodisomies (UPIDs), with a median of three changes (range 0-11) per case. The genes recurrently deleted comprised CDKN2A, CDKN2B, LEF1, PTEN, RBI, and STIL. No case had a whole chromosome UPID; in fact, literature data show that this is a rare phenomenon in T-ALL. However, segmental UPIDs (sUPIDs) were seen in 42% of our cases, with most being sUPID9p that always were associated with homozygous CDKN2A deletions, with a heterozygous deletion occurring prior to the sUPID9p in all instances. Among the 75 genes sequenced, 14 (19%) were mutated in 28 (72%) of 39 analyzed cases. The genes targeted are involved in signaling transduction, epigenetic regulation, and transcription. In some cases, NOTCH1 mutations were seen in minor subclones and lost at relapse; thus, such mutations can be secondary events.

    Conclusions: Deep sequencing and SNP array analyses of T-ALL revealed lack of wUPIDs, a high proportion of sUPID9p targeting CDKN2A, NOTCH1 mutations in subclones, and recurrent mutations of genes involved in signaling transduction, epigenetic regulation, and transcription.

  • 36. Karrman, Kristina
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Andersen, Mette K
    Autio, Kirsi
    Borgström, Georg
    Heim, Sverre
    Heinonen, Kristina
    Hovland, Randi
    Kerndrup, Gitte
    Johansson, Bertil
    High incidence of the ETV6/RUNX1 fusion gene in paediatric precursor B-cell acute lymphoblastic leukaemias with trisomy 21 as the sole cytogenetic change: a Nordic series of cases diagnosed 1989-2005.2006Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 135, nr 3, s. 352-4Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trisomy 21 is common in ETV6/RUNX1-positive acute lymphoblastic leukaemia (ALL); both these aberrations are associated with a favourable outcome. The prognostic impact of +21 as a sole cytogenetic change could be due to a cryptic t(12;21)(p13;q22). The occurrence of ETV6/RUNX1 was determined in 66 childhood ALLs with an acquired +21 and a chromosome number <51. ETV6/RUNX1 was found in 45% of cases and in the majority (10/18; 56%) of ALLs with sole +21. Event-free survival did not differ between the t(12;21)-positive and -negative cases. Thus, the prognostic impact of +21 is not attributable to cryptic ETV6/RUNX1.

  • 37.
    Karrman, Kristina
    et al.
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Heyman, Mats
    Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Andersen, Mette K
    Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark.
    Autio, Kirsi
    Department of Pathology and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
    Blennow, Elisabeth
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Borgström, Georg
    Department of Pathology and Clinical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
    Ehrencrona, Hans
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Faculty of Medicine, University of Oslo, Oslo, Norway.
    Heinonen, Kristiina
    Genetic Laboratory, ISLAB, Kuopio, Finland.
    Hovland, Randi
    Center of Medical Genetics and Molecular Medicine, Haukeland University Hospital, Helse-Bergen HF, Norway.
    Johannsson, Johann H
    Department of Clinical Genetics and Cytogenetics, University Hospital, Reykjavik, Iceland.
    Kerndrup, Gitte
    Department of Pathology, Odense University Hospital, Odense, Denmark.
    Nordgren, Ann
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Palmqvist, Lars
    Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, Göteborg, Sweden.
    Johansson, Bertil
    Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
    Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome2009Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 48, nr 9, s. 795-805Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.

  • 38.
    Kuchinskaya, Ekaterina
    et al.
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Heyman, Mats
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Nordgren, Ann
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Söderhäll, Stefan
    Astrid Lindgren’s Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Wehner, Peder
    Paediatric Oncology Department, University Hospital, Odense, Denmark.
    Vettenranta, Kim
    Paediatric Oncology Department, University Hospital, Tampere, Finland.
    Jonsson, Olafur
    Childrens Hospital, Hringsins, Landspitali, Hringbraut, Reykjavik, Iceland.
    Wesenberg, Finn
    Barneklinikken, Rikshospitalet, Oslo, Norway.
    Sahlén, Sigrid
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Nordenskjöld, Magnus
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Blennow, Elisabeth
    Centre of Molecular Medicine and Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol2011Ingår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 152, nr 5, s. 615-622Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) - 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15·7%). Homozygous deletions were found in 19·7% of T-ALL and 4·0% of BCP-ALL; hemizygous deletions were found in 18·2% and 11·7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement.

  • 39.
    Lemez, Petr
    et al.
    1Department of Hematology and Blood Transfusion, Hospital Jihlava, Jihlava, Czech Republic.
    Attarbaschi, Andishe
    St. Anna Children’s Hospital, Vienna, Austria.
    Béné, Marie C
    GEIL-Laboratoire d’Immunologie du CHU & Faculte´ de Me´ decine, Nancy, France.
    Bertrand, Yves
    Department of Pediatric Hematology, Hopital Debrousse,.
    Castoldi, Gianluigi
    Institute of Hematology, University of Ferrara, Ferrara, Italy.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Garand, Richard
    Laboratory of Hematology, University Hospitals, Nantes, France.
    Haas, Oskar A
    St. Anna Children’s Hospital, Vienna, Austria.
    Kagialis-Girard, Sandrine
    Hematological Laboratory, Hopital Debrousse, Lyon, France.
    Ludwig, Wolf-Dieter
    Department of Hematology-Oncology-Tumor Biology, HELIOS Clinic, Berlin-Buch, Germany.
    Matutes, Estella
    Department of Haematological Oncology, Royal Marsden Hospital, London, UK.
    Mejstríková, Ester
    Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic.
    Pages, Marie-Pierre
    Hematological Laboratory, Hopital Debrousse, Lyon, France.
    Pickl, Winfried
    Institute of Immunology, University of Vienna, Vienna, Austria.
    Porwit, Anna
    Department of Pathology, Karolinska University Hospital and Institute, Stockholm, Sweden.
    Orfao, Alberto
    Servicio di Citometria, University of Salamanca, Salamanca, Spain.
    Schabath, Richard
    Department of Hematology-Oncology-Tumor Biology, HELIOS Clinic, Berlin-Buch, Germany.
    Starý, Jan
    Department of Pediatric Hematology and Oncology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic.
    Strobl, Herbert
    Institute of Immunology, University of Vienna, Vienna, Austria.
    Talmant, Pascaline
    Laboratory of Hematology, University Hospitals, Nantes, France.
    van't Veer, Mars B
    Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.
    Zemanová, Zuzana
    Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic.
    Childhood near-tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases2010Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 85, nr 4, s. 300-308Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVES: Patients with near-tetraploid (karyotype: 81 - 103 chromosomes) acute lymphoblastic leukemia (NT-ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL. METHODS: The members of the European Group for Immunophenotyping of Leukemias (EGIL) searched retrospectively their databases for NT-ALL patients. RESULTS: We collected data of 36 European children from seven European countries with NT-ALL diagnosed since 1992. All patients reached complete remission (CR) after induction chemotherapy. Their blasts were negative for peroxidase and BCR-ABL1. Ten children were diagnosed as T-cell ALL (T-ALL) EGIL categories (T-I n=2, T-II n=2, T-III n=3, T-IV n=3) and four displayed various structural chromosomal abnormalities. Eight of 10 T-ALL remained in 1st CR; one died in CR from sepsis and one is alive in 2nd CR. Median survival was 88 (7-213) months. B-cell precursor (BCP) ALL was diagnosed in 26 children. Thirteen were positive for ETV6-RUNX1 and are alive in 1st CR for 32-147 months. Ten children were ETV6-RUNX1 negative and remained in 1st CR for 16-163 months. One girl with hypodiploid and NT metaphases and ETV6-RUNX1-negative BCP-ALL and one of two boys with NT-BCP-ALL not examined for ETV6-RUNX1 died of infection after stem cell transplantation in 2nd/3rd CR. Secondary myelodysplastic syndrome developed in two patients with NT-BCP-ALL. CONCLUSIONS: Our data demonstrate immunophenotypic, cytogenetic, and molecular heterogeneity of NT-ALL and favorable prognosis of most NT-ALL across different immunophenotypic and/or genetic ALL subtypes.

  • 40. Levinsen, Mette
    et al.
    Taskinen, Mervi
    Abrahamsson, Jonas
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Frandsen, Thomas L.
    Harila-Saari, Arja
    Heyman, Mats
    Jonsson, Olafur G.
    Lahteenmaki, Paeivi M.
    Lausen, Birgitte
    Vaitkeviciene, Goda
    Asberg, Ann
    Schmiegelow, Kjeld
    Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia2014Ingår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, nr 8, s. 1416-1421Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) remains a therapeutic challenge. Procedure To explore leukemia characteristics of patients with CNS involvement at ALL diagnosis, we analyzed clinical features and early treatment response of 744 patients on Nordic-Baltic trials. CNS status was classified as CNS1 (no CSF blasts), CNS2 (<5 leukocytes/mu l CSF with blasts), CNS3 (5 leukocytes/mu l with blasts or signs of CNS involvement), TLP+ (traumatic lumbar puncture with blasts), and TLP- (TLP with no blasts). Results Patients with CNS involvement had higher leukocyte count compared with patients with CNS1 (P<0.002). Patients with CNS3 more often had T-ALL (P<0.001) and t(9;22)(q34;q11)[BCR-ABL1] (P<0.004) compared with patients with CNS1. Among patients with CNS involvement headache (17%) and vomiting (14%) were most common symptoms. Symptoms or clinical findings were present among 27 of 54 patients with CNS3 versus only 7 of 39 patients with CNS2 and 15 of 75 patients with TLP+ (P<0.001). The majority of patients with CNS involvement received additional induction therapy. The post induction bone marrow residual disease level did not differ between patients with CNS involvement and patients with CNS1 (0.15). The 12-year event-free survival for patients with leukemic mass on neuroimaging did not differ from patients with negative or no scan (0.50 vs. 0.60; P=0.7) or between patients with symptoms or signs suggestive of CNS leukemia and patients without such characteristics (0.50 vs. 0.61; P=0.2). Conclusion CNS involvement at diagnosis is associated with adverse prognostic features but does not indicate a less chemosensitive leukemia.

  • 41.
    Li, Aihong
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rosenquist, Richard
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Minimal residual disease quantification in childhood acute lymphoblastic leukemia by real-time polymerase chain reaction using the SYBR green dye.2002Ingår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 30, nr 10, s. 1170-1177Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    OBJECTIVE: Clone specific immunoglobulin (Ig) and T-cell receptor (TCR) gene sequences can be used as molecular targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). Real-time quantitative PCR (RQ-PCR) with no need for post-PCR processing is an attractive approach for detection and quantification of specific DNA or RNA sequences. In the present study we evaluated a real-time PCR-based technology for MRD quantification in children with precursor-B ALL. MATERIALS AND METHODS: DNA samples from 36 children with newly diagnosed precursor-B ALL were available for molecular analysis. All patients were uniformly treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) protocols from 1992. A real-time PCR assay was applied for MRD quantification using LightCycler technology and the SYBR green fluorescent dye for detection of clone-specific Ig and TCR gene rearrangements as target sequences. The specificity of the PCR products was verified by melting curve analysis. RESULTS: Thirty-four of the 36 children with precursor-B ALL (94%) displayed at least one clonal Ig heavy chain (IgH) or TCR gene sequence useful as a molecular target. These clone-specific targets were successfully applied for real-time PCR quantification in all but one patient. Melting curve analysis was important for identifying all specific PCR products. In 32 pediatric precursor-B-ALL patients an MRD level >/=10(-3) at day 29 during induction treatment was significantly correlated with later bone marrow relapse (p = 0.0025). CONCLUSIONS: Real-time PCR using clone-specific primers and the SYBR green dye for detection is a feasible technique for identifying patients at risk for relapse. This approach provides an easily applicable tool for detection of IgH/TCR gene rearrangements in the routine setting. Melting curve analysis allowed clear distinction between specific rearrangements and unspecific background signals.

  • 42.
    Li, Aihong
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rosenquist, R
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Holmberg, D
    Lindh, Jack
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Löfvenberg, E
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Clonal rearrangements in childhood and adult precursor B acute lymphoblastic leukemia: a comparative polymerase chain reaction study using multiple sets of primers.1999Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 63, nr 4, s. 211-8Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Ig heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements were investigated by polymerase chain reaction (PCR) amplification of diagnostic tumour samples from 91 patients (57 children and 34 adults, with cut-off at age 16) with precursor B acute lymphoblastic leukemia (ALL). Using primers directed to the framework regions (FR) 1, 2 and 3 of the IgH gene, clonal IgH rearrangements were observed in 82, 58 and 58%, respectively, whereas clonality was presented in 45 and 27% using primers hybridising to the TCR delta and gamma genes. A combination of all five primer sets used resulted in 96% positive cases (children 100%, adults 88%). The frequency of clonal IgH rearrangements correlated to patient age with a significantly lower fraction of positive cases in the adult group. The concomitant usage of more than one V(H) family gene was similar for childhood and adult ALL, and an over-representation of V(H)6 rearrangements was found in childhood ALL. Twenty-five out of 91 cases (27%) displayed an oligoclonal pattern for either IgH or TCR gene rearrangements (children 37%, adults 12%). A comparative analysis of samples from different compartments was performed in 23 patients, and differences between two or three compartments were observed in seven cases. Unexpectedly large, clonally appearing PCR products of 540-715 bp were found in three leukemias and sequence analysis verified their clonal nature. In summary, using multiple sets of primers clonal rearrangements of IgH and TCR genes can be detected in a very high frequency, including previously neglected large size PCR products. A common heterogeneity was demonstrated in different compartments reflecting ongoing clonal evolution, which can make detection of minimal residual disease (MRD) in ALL troublesome. Therefore, we suggest that a minimum of three targets should be used to minimise false-negative results.

  • 43.
    Li, Aihong
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Rosenquist, R
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Lindh, Jack
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection.2001Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 25, nr 12, s. 1033-45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic instability has important implications for detection of minimal residual disease (MRD) when the target is a clonal genetic marker revealed at diagnosis. A successful MRD detection approach requires a stable marker and for lymphoid leukemias clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes are commonly used. In the present study, Ig heavy chain (IgH) and TCR (gamma and delta) genes were studied in 18 consecutive, relapsing precursor-B ALL patients. At least one clonal rearrangement was found in all cases at presentation (IgH 94%, TCRgamma 39% and TCRdelta 28%). An altered rearrangement pattern between diagnosis and relapse was demonstrated in 14 patients (78%). At least one stable molecular target was found in 13 out of 18 cases (72%). Clonal differences between diagnostic and relapse samples were explained by: (1) loss of original rearrangements; (2) V(H) to DJ(H) joining; (3) V(H) gene replacement; (4) appearance of new rearrangements. In two cases with apparently new IgH gene rearrangements at relapse extended sequencing of the diagnostic samples revealed minor clonal rearrangements identical to the relapse clones. Interestingly, one patient displayed instability on both the IgH and TCR gene loci, whereas a stable Igkappa rearrangement was found at presentation and relapse. These data show that clonal diversity is common in precursor-B ALL and strongly suggest that MRD detection should include multiple gene targets to minimize false-negative samples. Even so, five of our 18 relapse cases (28%) lacked stable clonal markers and should have been unsuitable for MRD detection.

  • 44. Lindqvist, C. Marten
    et al.
    Lundmark, Anders
    Nordlund, Jessica
    Freyhult, Eva
    Ekman, Diana
    Almlof, Jonas Carlsson
    Raine, Amanda
    Overnas, Elin
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grander, Dan
    Heyman, Mats
    Palle, Josefine
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Nordic Society of Pediatric Hematology and Oncology.
    Lonnerholm, Gudmar
    Berglund, Eva C.
    Syvanen, Ann-Christine
    Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes2016Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 39, s. 64071-64088Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

  • 45. Lindqvist, Carl Marten
    et al.
    Nordlund, Jessica
    Ekman, Diana
    Johansson, Anna
    Moghadam, Behrooz Torabi
    Raine, Amanda
    Overnas, Elin
    Dahlberg, Johan
    Wahlberg, Per
    Henriksson, Niklas
    Abrahamsson, Jonas
    Frost, Britt-Marie
    Grander, Dan
    Heyman, Mats
    Larsson, Rolf
    Palle, Josefine
    Soderhall, Stefan
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Lonnerholm, Gudmar
    Syvanen, Ann-Christine
    Berglund, Eva C.
    The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing2015Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 1, s. 118-128Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

  • 46. Lund Laursen, Anne Cathrine
    et al.
    Sandahl, Julie Damgaard
    Kjeldsen, Eigil
    Abrahamsson, Jonas
    Asdahl, Peter
    Ha, Shau-Yin
    Heldrup, Jesper
    Jahnukainen, Kirsi
    Jónsson, Ólafur G
    Lausen, Birgitte
    Palle, Josefine
    Zeller, Bernward
    Forestier, Erik
    Department of Medical Biosciences, Clinical Genetics, Umeå University Hospital, Umeå, Sweden.
    Hasle, Henrik
    Trisomy 8 in pediatric acute myeloid leukemia: A NOPHO-AML study2016Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, nr 9, s. 719-726Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone.

  • 47. Lundin, Catarina
    et al.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Andersen, Mette Klarskov
    Autio, Kirsi
    Barbany, Gisela
    Cavelier, Lucia
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heim, Sverre
    Heinonen, Kristiina
    Hovland, Randi
    Johannsson, Johann H.
    Kjeldsen, Eigil
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nordgren, Ann
    Palmqvist, Lars
    Johansson, Bertil
    Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries2014Ingår i: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 7, s. 32-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background:

    Children with Down syndrome (DS) have an increased risk for acute lymphoblastic leukemia (ALL). Although previous studies have shown that DS-ALL differs clinically and genetically from non-DS-ALL, much remains to be elucidated as regards genetic and prognostic factors in DS-ALL.

    Methods:

    To address clinical and genetic differences between DS-ALL and non-DS-ALL and to identify prognostic factors in DS-ALL, we ascertained and reviewed all 128 pediatric DS-ALL diagnosed in the Nordic countries between 1981 and 2010. Their clinical and genetic features were compared with those of the 4,647 B-cell precursor (BCP) ALL cases diagnosed during the same time period.

    Results:

    All 128 DS-ALL were BCP ALL, comprising 2.7% of all such cases. The 5-year event-free survival (EFS) and overall survival (OS) were significantly (P = 0.026 and P = 0.003, respectively) worse for DS-ALL patients with white blood cell counts >= 50 x 10(9)/l. The age distributions varied between the DS and non-DS cases, with age peaks at 2 and 3 years, respectively; none of the DS patients had infant ALL (P = 0.029). The platelet counts were lower in the DS-ALL group (P = 0.005). Abnormal karyotypes were more common in non-DS-ALL (P < 0.0001), and there was a significant difference in the modal number distribution, with only 2% high hyperdiploid DS-ALL cases (P < 0.0001). The 5-year EFS and 5-year OS were significantly worse for DS-ALL (0.574 and 0.691, respectively) compared with non-DS-ALL (0.783 and 0.894, respectively) in the NOPHO ALL-1992/2000 protocols (P < 0.001).

    Conclusions:

    The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.

  • 48. Lundin, Catarina
    et al.
    Hjorth, Lars
    Behrendtz, Mikael
    Nordgren, Ann
    Palmqvist, Lars
    Andersen, Mette Klarskov
    Biloglav, Andrea
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Paulsson, Kajsa
    Johansson, Bertil
    High frequency of BTG1 deletions in acute lymphoblastic leukemia in children with down syndrome2012Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 51, nr 2, s. 196-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Previous cytogenetic studies of myeloid and acute lymphoblastic leukemias in children with Down syndrome (ML-DS and DS-ALL) have revealed significant differences in abnormality patterns between such cases and acute leukemias in general. Also, certain molecular genetic aberrations characterize DS-related leukemias, such as GATA1 mutations in ML-DS and deregulation of the CRLF2 gene in DS-ALL. Whether microdeletions/microduplications also vary between DS and non-DS cases is presently unclear. To address this issue, we performed single nucleotide polymorphism array analyses of eight pediatric ML-DS and 17 B-cell precursor DS-ALL. In the ML-DS cases, a total of 29 imbalances (20 gains and nine losses) and two partial uniparental isodisomies (pUPDs) were detected. None of the 11 small (defined as <10 Mb) imbalances were recurrent, nor were the pUPDs, whereas of the 18 large aberrations, three were recurrentdup(1q), +8 and +21. In contrast, several frequent changes were identified in the DS-ALL cases, which harbored 82 imbalances (30 gains and 52 losses) and four pUPDs. Of the 40 large changes, 28 were gains and 12 losses, with +X, dup(Xq), dup(1q), del(7p), dup(8q), del(9p), dup(9p), del(12p), dup(17q), and +21 being recurrent. Of the 40 microdeletions identified, several targeted specific genes, with the following being repeatedly deleted: BTG1 and CDKN2A/B (29% of cases), ETV6, IKZF1, PAX5 and SERP2 (18%), and BTLA, INPP4B, P2RY8, and RB1 (12%). Loss of the SERP2 and INPP4B genes, encoding the stress-associated endoplasmic reticulum protein family member 2 and the inositol polyphosphate 4-phosphatase-II, respectively, has previously never been implicated in leukemia. Although deletions of the other genes have been associated with ALL, the high frequency of BTG1 loss is a novel finding. Such deletions may characterize a clinical subgroup of DS-ALL, comprising mainly boys with a high median age. In conclusion, ML-DS and DS-ALL are genetically distinct, with mainly gains in ML-DS and deletions in DS-ALL. Furthermore, DS-ALL is characterized by several recurrent gene deletions, with BTG1 loss being particularly frequent. (C) 2011 Wiley Periodicals, Inc.

  • 49. Lönnerholm, G
    et al.
    Nordgren, A
    Frost, B-M
    Jonsson, O G
    Kanerva, J
    Nygaard, R
    Schmiegelow, K
    Larsson, R
    Forestier, E
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Dic(9;20)(p13;q11) in childhood acute lymphoblastic leukaemia is related to low cellular resistance to asparaginase, cytarabine and corticosteroids.2008Ingår i: Leukemia, ISSN 1476-5551Artikel i tidskrift (Övrigt vetenskapligt)
  • 50.
    Lönnerholm, Gudmar
    et al.
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Thörn, Ingrid
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sundström, Christer
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Frost, Britt-Marie
    Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
    Abrahamsson, Jonas
    Qween Silvias Children's Hospital, Gothenburg, Sweden.
    Behrendtz, Mikael
    Department of Pediatrics, University Hospital, Linköping, Sweden.
    Heldrup, Jesper
    Department of Pediatrics, Lund University Hospital, Lund, Sweden.
    Jacobsson, Stefan
    Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Li, Aihong
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Olofsson, Tor
    Division of Hematology & Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
    Porwit, Anna
    Department of Pathology, Karolinska University Hospital, Stockholm, Sweden.
    Söderhäll, Stefan
    Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Rolf
    Department of Medical Sciences, Section of Pharmacology, University Hospital, Uppsala, Sweden.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    In vitro cellular drug sensitivity at diagnosis is correlated to minimal residual disease at end of induction therapy in childhood acute lymphoblastic leukemia2009Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 33, nr 1, s. 46-53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Leukemic cells from 85 children with newly diagnosed precursor B-lineage ALL were tested for in vitro drug sensitivity to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. There was a significant correlation between MRD day 29 and in vitro sensitivity to prednisolone (p<0.001) and doxorubicin (p=0.017), drugs administered during induction therapy. In patients with t(12;21) (n=20), in vitro sensitivity to doxorubicin was an independent factor for MRD <0.1% (p=0.031; R(2)=0.66). Thus, data show that in vitro drug sensitivity at diagnosis is correlated to cell kill during induction therapy as measured by MRD day 29.

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