Erik Forestier

Umeå University, Umeå, Västerbotten, Sweden

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Publications (133)738.85 Total impact

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    ABSTRACT: Purpose: This retrospective cohort study aimed to determine the predictive relevance of clinical characteristics, additional cytogenetic aberrations, and cKIT and RAS mutations, as well as to evaluate whether specific treatment elements were associated with outcomes in pediatric t(8;21)-positive patients with acute myeloid leukemia (AML). Patients and methods: Karyotypes of 916 pediatric patients with t(8;21)-AML were reviewed for the presence of additional cytogenetic aberrations, and 228 samples were screened for presence of cKIT and RAS mutations. Multivariable regression models were used to assess the relevance of anthracyclines, cytarabine, and etoposide during induction and overall treatment. End points were the probability of achieving complete remission, cumulative incidence of relapse (CIR), probability of event-free survival, and probability of overall survival. Results: Of 838 patients included in final analyses, 92% achieved complete remission. The 5-year overall survival, event-free survival, and CIR were 74%, 58%, and 26%, respectively. cKIT mutations and RAS mutations were not significantly associated with outcome. Patients with deletions of chromosome arm 9q [del(9q); n = 104] had a lower probability of complete remission (P = .01). Gain of chromosome 4 (+4; n = 21) was associated with inferior CIR and survival (P < .01). Anthracycline doses greater than 150 mg/m(2) and etoposide doses greater than 500 mg/m(2) in the first induction course and high-dose cytarabine 3 g/m(2) during induction were associated with better outcomes on various end points. Cumulative doses of cytarabine greater than 30 g/m(2) and etoposide greater than 1,500 mg/m(2) were associated with lower CIR rates and better probability of event-free survival. Conclusion: Pediatric patients with t(8;21)-AML and additional del(9q) or additional +4 might not be considered at good risk. Patients with t(8;21)-AML likely benefit from protocols that have high doses of anthracyclines, etoposide, and cytarabine during induction, as well as from protocols comprising cumulative high doses of cytarabine and etoposide.
    No preview · Article · Nov 2015 · Journal of Clinical Oncology

  • No preview · Article · Oct 2015 · Haematologica
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    ABSTRACT: Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the upfront therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following ALL relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications; and identify additional prognostic factors for overall survival. In total 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included. There were no statistically significant differences in outcome between the upfront protocols or between the relapse-protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing 2002-2011 was 57.5 +/- 3.4% but 44.7 +/- 3.2% (p<0.001) if relapse occurred 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ≥10 years, unfavorable cytogenetics and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0 +/- 10.6%) which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, development of novel approaches is urgent to increase survival in relapsed childhood acute lymphoblastic leukemia.
    Full-text · Article · Oct 2015 · Haematologica
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    ABSTRACT: Background Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited.ProcedureWe investigated disease characteristics and outcome for de novo AML patients 10–30 years old treated in pediatric or adult departments. We included 166 patients 10–18 years of age with AML treated according to the pediatric NOPHO-protocols (1993–2009) compared with 253 patients aged 15–30 years treated in hematology departments (1996–2009) in the Nordic countries.ResultsThe incidence of AML was 4.9/million/year for the age group 10–14 years, 6.5 for 15–18 years, and 6.9 for 19–30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52–68%) for pediatric patients compared to 65% (58–70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor.Conclusions No difference was found in outcome for AML patients age 10–30 years treated according to pediatric as compared to adult protocols. Pediatr Blood Cancer 2015; 9999:1–10 © 2015 Wiley Periodicals, Inc.
    No preview · Article · Aug 2015 · Pediatric Blood & Cancer
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    ABSTRACT: 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 2000-2009 were treated with higher doses of cytarabine and had better EFS (P=0.037) and OS (P=0.003) than those diagnosed in 1989-1999, but outcomes of patients diagnosed in 2000-2004 and 2005-2009 were similar. 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%), 47-50 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 analysis for EFS and OS, 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 and 11q23/MLL except t(9;11). Risk-based innovative therapy is needed to improve patient outcomes. Copyright © 2015 American Society of Hematology.
    No preview · Article · Jul 2015 · Blood
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    ABSTRACT: 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. 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. 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. 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.
    Full-text · Article · Apr 2015 · Journal of Hematology & Oncology
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    ABSTRACT: 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.This article is protected by copyright. All rights reserved
    Full-text · Article · Jan 2015 · Human Mutation
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    ABSTRACT: Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)(p13q22), CBFB–MYH11, are considered as favorable risk factors in AML with superior event-free survival (EFS) and overall survival (OS). However, within the AML protocol from the Nordic society of pediatric hematology/oncology (NOPHO) from 2004 we observed a decrease in EFS for t(8;21) AML. Material. We analyzed all children with t(8;21) or inv(16) treated on NOPHO-AML 93 and NOPHO-AML 2004 from Denmark, Finland, Iceland, Norway, and Sweden from 1993 to 2013 and patients from countries later joining the NOPHO-AML 2004 protocol; Estonia (2004), Hong Kong (2007), Belgium and the Netherlands (2010). The choice of anthracycline during induction changed from two courses including doxorubicin (75 mg/m2 in each course), Dox-Dox, in the NOPHO-AML 93 to idarubicin (36 mg/m2) and mitoxantrone (30 mg/m2), Ida-Mitox, in NOPHO-AML 04. After the observation of a decrease in EFS in patients with t(8;21) in late 2010 it was recommended to give fludarabine, cytarabine, and DaunoXome (liposomal daunorubicin 180 mg/m2) as second induction to patients with t(8;21); Ida-DNX. Results. From 1993 to 2013 a total of 90 children, median age 9.1 years range 1-16, with t(8;21) AML were treated with Dox-Dox (n=25), Ida-Mitox (n=41), and Ida-DNX (n=24). Hematopoietic stem cell transplantation was given to 10 patients (11%), mostly with sibling donors in the NOPHO-AML 93 protocol (n=7). A reduction of the 3-year EFS was noted in patients treated with Ida-Mitox (41%) compared with Dox-Dox (64%). Those treated with Ida-DNX had significantly higher 3-year EFS of 87% (Figure). The events in t(8;21) AML on Ida-Mitox were relapses (n=20), death in CR1 (n=2), and secondary malignancy (n=2). The salvage rate for relapsed t(8;21) patients remained high and the overall favorable OS did not change significantly (Figure). From 1993 to 2013 a total of 58 children with inv(16) AML were treated with Dox-Dox (n=18) and Ida-Mitox (n=40). No significant changes in EFS (72% vs. 65%) or OS (89% vs. 79%) were observed for patients with inv(16). Conclusion. Despite the overall favorable survival in t(8;21) the present study suggests that the choice of anthracycline during induction may be of major importance for the EFS in t(8;21) AML. Idarubicin and mitoxantrone during induction was associated with an inferior EFS compared with doxorubicin in t(8;21) AML. DaunoXome combined with fludarabine and cytarabine seemed to be particular effective during induction therapy in t(8;21) AML.
    Full-text · Conference Paper · Dec 2014
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    ABSTRACT: We present a method that utilizes DNA methylation profiling for prediction of the cytogenetic subtypes of acute lymphoblastic leukemia (ALL) cells from pediatric ALL patients. The primary aim of our study was to improve risk stratification of ALL patients into treatment groups using DNA methylation as a complement to current diagnostic methods. A secondary aim was to gain insight into the functional role of DNA methylation in ALL. We used the methylation status of ~450,000 CpG sites in 546 well-characterized patients with T-ALL or seven recurrent B-cell precursor ALL subtypes to design and validate sensitive and accurate DNA methylation classifiers. After repeated cross-validation, a final classifier was derived that consisted of only 246 CpG sites. The mean sensitivity and specificity of the classifier across the known subtypes was 0.90 and 0.99, respectively. We then used DNA methylation classification to screen for subtype membership of 210 patients with undefined karyotype (normal or no result) or non-recurrent cytogenetic aberrations ('other' subtype). Nearly half (n = 106) of the patients lacking cytogenetic subgrouping displayed highly similar methylation profiles as the patients in the known recurrent groups. We verified the subtype of 20% of the newly classified patients by examination of diagnostic karyotypes, array-based copy number analysis, and detection of fusion genes by quantitative polymerase chain reaction (PCR) and RNA-sequencing (RNA-seq). Using RNA-seq data from ALL patients where cytogenetic subtype and DNA methylation classification did not agree, we discovered several novel fusion genes involving ETV6, RUNX1, and PAX5. Our findings indicate that DNA methylation profiling contributes to the clarification of the heterogeneity in cytogenetically undefined ALL patient groups and could be implemented as a complementary method for diagnosis of ALL. The results of our study provide clues to the origin and development of leukemic transformation. The methylation status of the CpG sites constituting the classifiers also highlight relevant biological characteristics in otherwise unclassified ALL patients.
    Full-text · Conference Paper · Dec 2014
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    ABSTRACT: We report the first large series (n = 596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n = 237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n = 251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n = 80; 18%) and MN 43–45 (n = 48; 8%). No cases had MN less than 43. Hyperdiploid AML with MN 48–65 comprised 11% of all cases and was associated with early onset (median age 2 years), female sex (57%), and a dominance of acute megakaryoblastic leukemia (AMKL) (29%). Hypodiploidy constituted 8% of all AML and was associated with older age (median age 9 years), male predominance (60%), FAB M2 (56%), and t(8;21)(q22;q22) (56%) with loss of sex chromosomes. Inferior outcome was observed for hypodiploid cases (5-year event-free survival 40% and 5-year overall survival 40%) but did not reach statistical significance. Chromosomes were gained in a nonrandom pattern, where chromosomes 8, 21, 19, and 6 were the most commonly gained. In conclusion, based on MNs, two cytogenetic subgroups with characteristic clinical features are described; hypodiploidy found in 8% and associated with high median age, male sex, t(8;21)(q22;q22), and FAB M2 and possibly associated with inferior outcome (P = 0.13), and hyperdiploidy with MN 48–65 in 11% associated with early onset, female sex, and AMKL. © 2014 Wiley Periodicals, Inc.
    No preview · Article · Aug 2014 · Genes Chromosomes and Cancer
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    ABSTRACT: 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/µl CSF with blasts), CNS3 (≥5 leukocytes/µl 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 (P > 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.
    No preview · Article · Aug 2014 · Pediatric Blood & Cancer
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    ABSTRACT: 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.
    Full-text · Article · Jul 2014 · Neoplasia (New York, N.Y.)

  • No preview · Conference Paper · Jun 2014
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    ABSTRACT: 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. 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. 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 109/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). The present study adds further support for genetic and clinical differences between DS-ALL and non-DS-ALL.
    Full-text · Article · Apr 2014 · Journal of Hematology & Oncology
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    ABSTRACT: 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. 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. 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 9.2 ± 1.9 (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. 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. © 2013 Wiley Periodicals, Inc.
    Full-text · Article · Mar 2014 · Pediatric Blood & Cancer
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    ABSTRACT: Acute myeloid leukemia with t(6;9)(p22;q34) is listed as a distinct entity in the 2008 WHO classification, but little is known about the clinical implications of t(6;9)-positive myeloid leukemia in children. This international multicenter study present clinical and genetic characteristics on 62 pediatric patients with t(6;9)/DEK-NUP214 rearranged myeloid leukemia; 54 diagnosed as acute myeloid leukemia, representing <1% of all childhood acute myeloid leukemia, and 8 as myelodysplastic syndrome. The t(6;9)/DEK-NUP214 was associated with relative late onset (median age 10.4 years), male predominance (sex ratio 1.7), FAB M2 (54%), myelodysplasia (100%), and FLT3-ITD (42%). Outcome was substantially better than previously reported with a 5-year event-free survival of 32%, 5-year overall survival of 53%, and a 5-year cumulative incidence of relapse of 57%. Hematopoietic stem cell transplant in 1st complete remission improved the 5-year event-free survival compared with chemotherapy alone (68% vs. 18%; P<0.01) but not the overall survival (68% vs. 54%, P=0.48). FLT3-ITD had a non-significant negative effect on 5-year overall survival vs. non-mutated cases (22% vs. 62%; P=0.13). Gene expression profiling showed a unique signature characterized by significantly higher expression of the EYA3, SESN1, PRDM2/RIZ, and HIST2H4 genes. In conclusion, t(6;9)/DEK-NUP214 represents a unique subtype of acute myeloid leukemia with high risk of relapse, high frequency of FLT3-ITD, and a specific gene expression signature.
    No preview · Article · Jan 2014 · Haematologica
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    ABSTRACT: 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. 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. 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.
    Full-text · Article · Dec 2013 · BMC Genomics
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    ABSTRACT: Children with Down syndrome (DS) have an increased risk of B-cell precursor acute lymphoblastic leukemia (BCP-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 1995-2004. Non-DS BCP-ALL patients from the DCOG and BFM were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26±2% vs. 15±1%; p<0.001) and 2-year treatment-related mortality (TRM) (7±1% vs. 2.0±<1%; p<0.0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64±2% vs. 81±2%; p<0.0001) and overall survival (74±2% vs. 89±1%; p<0.0001). Independent favorable prognostic factors include age<6 years (hazard ratio [HR]=0.58, p=0.002), white blood cell count (WBC) <10x10(9)/L (HR=0.60, p=0.005) and ETV6-RUNX1 (HR=0.14; p=0.006) for EFS, age (HR=0.48, p<0.001), ETV6-RUNX1 (HR 0.1, p=0.016) and high hyperdiploidy (HeH) (HR 0.29, p=0.04) 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.
    Full-text · Article · Nov 2013 · Blood
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    ABSTRACT: 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, which 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 WHO as a distinct entity of BCP-ALL.Leukemia accepted article preview online, 29 October 2013; doi:10.1038/leu.2013.317.
    Full-text · Article · Oct 2013 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood. We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status. Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.
    Full-text · Article · Sep 2013 · Genome biology

Publication Stats

3k Citations
738.85 Total Impact Points

Institutions

  • 1994-2015
    • Umeå University
      • • Department of Medical Biosciences
      • • Department of Clinical Sciences
      Umeå, Västerbotten, Sweden
  • 2006-2011
    • University of Helsinki
      • The Hospital for Children and Adolescents
      Helsinki, Uusimaa, Finland
  • 2008
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
  • 1988-1990
    • Sundsvall Hospital
      Sundsvall, Västernorrland, Sweden