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Forestier, Erik
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Publications (10 of 85) Show all publications
Wennström, L., Edslev, P. W., Abrahamsson, J., Nørgaard, J. M., Fløisand, Y., Forestier, E., . . . Hasle, H. (2016). Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries. Pediatric Blood & Cancer, 63(1), 83-92.
Open this publication in new window or tab >>Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 1, 83-92 p.Article in journal (Refereed) Published
Abstract [en]

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. Procedure: We 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. Results: The 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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2016
Keyword
acute myeloid leukemia, adolescents, age, outcome, young adults
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-114613 (URN)10.1002/pbc.25713 (DOI)000367097800013 ()
Available from: 2016-02-08 Created: 2016-01-25 Last updated: 2017-11-30Bibliographically approved
Marincevic-Zuniga, Y., Zachariadis, V., Cavelier, L., Castor, A., Barbany, G., Forestier, E., . . . Nordlund, J. (2016). PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia [Letter to the editor]. Haematologica, 101(1), E20-E23.
Open this publication in new window or tab >>PAX5-ESRRB is a recurrent fusion gene in B-cell precursor pediatric acute lymphoblastic leukemia
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 1, E20-E23 p.Article in journal, Letter (Refereed) Published
Keyword
ESRRB, PAX5, pediatric acute lymphoblastic leukemia, RNA-sequencing, fusion genes
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-118804 (URN)10.3324/haematol.2015.132332 (DOI)000371220700006 ()26494837 (PubMedID)
Available from: 2016-04-08 Created: 2016-04-04 Last updated: 2017-11-30Bibliographically approved
Oskarsson, T., Soderhall, S., Arvidson, J., Forestier, E., Montgomery, S., Bottai, M., . . . Heyman, M. (2016). Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica, 101(1), 68-76.
Open this publication in new window or tab >>Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 1, 68-76 p.Article in journal (Refereed) Published
Abstract [en]

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia 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. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5 +/- 3.4%, but 44.7 +/- 3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, 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, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia.

Keyword
leukemia, treatment outcome, scandinavian and nordic countries
National Category
Pediatrics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-118803 (URN)10.3324/haematol.2015.131680 (DOI)000371220700021 ()26494838 (PubMedID)
Available from: 2016-04-11 Created: 2016-04-04 Last updated: 2017-11-30Bibliographically approved
Karrman, K., Castor, A., Behrendtz, M., Forestier, E., Olsson, L., Ehinger, M., . . . Johansson, B. (2015). 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 CDKN2A. Journal of Hematology & Oncology, 8, Article ID 42.
Open this publication in new window or tab >>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 CDKN2A
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2015 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 8, 42Article in journal (Refereed) Published
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.

Keyword
T-ALL, Pediatric, Genetic characterization, SNP array, Large-scale sequencing
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-103732 (URN)10.1186/s13045-015-0138-0 (DOI)000353761500001 ()
Available from: 2015-06-08 Created: 2015-05-28 Last updated: 2018-01-11Bibliographically approved
Nordlund, J., Backlin, C. L., Zachariadis, V., Cavelier, L., Dahlberg, J., Ofverholm, I., . . . Syvanen, A.-C. (2015). DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia. Clinical Epigenetics, 7, Article ID 11.
Open this publication in new window or tab >>DNA methylation-based subtype prediction for pediatric acute lymphoblastic leukemia
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2015 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 7, 11Article in journal (Refereed) Published
Abstract [en]

Background: 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. Results: We used the methylation status of similar to 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. Conclusions: 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.

Keyword
DNA methylation, Pediatric acute lymphoblastic leukemia, CpG site, Subtyping, Cytogenetics, RNA- q, 450 k array, epigenetics
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-101397 (URN)10.1186/s13148-014-0039-z (DOI)000350260800001 ()25729447 (PubMedID)
Available from: 2015-07-03 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved
Inaba, H., Zhou, Y., Abla, O., Adachi, S., Auvrignon, A., Beverloo, H. B., . . . Raimondi, S. C. (2015). Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study. Blood, 126(13), 1575-1584.
Open this publication in new window or tab >>Heterogeneous cytogenetic subgroups and outcomes in childhood acute megakaryoblastic leukemia: a retrospective international study
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2015 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 13, 1575-1584 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society of Hematology, 2015
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-111499 (URN)10.1182/blood-2015-02-629204 (DOI)000363481000012 ()26215111 (PubMedID)
Available from: 2015-12-01 Created: 2015-11-13 Last updated: 2017-12-01Bibliographically approved
Lindqvist, C. M., Nordlund, J., Ekman, D., Johansson, A., Moghadam, B. T., Raine, A., . . . Berglund, E. C. (2015). The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing. Human Mutation, 36(1), 118-128.
Open this publication in new window or tab >>The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing
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2015 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, no 1, 118-128 p.Article in journal (Refereed) Published
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.

Keyword
clonal heterogeneity, acute lymphoblastic leukemia, whole genome sequencing, RNA sequencing
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-99364 (URN)10.1002/humu.22719 (DOI)000347076700016 ()
Available from: 2015-03-04 Created: 2015-02-07 Last updated: 2018-01-11Bibliographically approved
Buitenkamp, T. D., Izraeli, S., Zimmermann, M., Forestier, E., Heerema, N. A., van den Heuvel-Eibrink, M. M., . . . Zwaan, C. M. (2014). Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group. Blood, 123(1), 70-77.
Open this publication in new window or tab >>Acute lymphoblastic leukemia in children with Down syndrome: a retrospective analysis from the Ponte di Legno study group
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, no 1, 70-77 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
American Society of Hematology, 2014
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-86068 (URN)10.1182/blood-2013-06-509463 (DOI)000329742300016 ()
Available from: 2014-02-17 Created: 2014-02-17 Last updated: 2017-12-06Bibliographically approved
Harrison, C. J., Moorman, A. V., Schwab, C., Carroll, A. J., Raetz, E. A., Devidas, M., . . . Haas, O. A. (2014). An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome. Leukemia, 28(5), 1015-1021.
Open this publication in new window or tab >>An international study of intrachromosomal amplification of chromosome 21 (iAMP21): cytogenetic characterization and outcome
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2014 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 5, 1015-1021 p.Article in journal (Refereed) Published
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.

Keyword
iAMP21, genetics, outcome, poor prognosis, BCP-ALL, chromosomal abnormalities
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-90864 (URN)10.1038/leu.2013.317 (DOI)000336661500005 ()
Available from: 2014-07-15 Created: 2014-07-01 Last updated: 2018-01-11Bibliographically approved
Hasle, H., Abrahamsson, J., De Bont, E. S., de Haas, V., De Moerloose, B., Forestier, E., . . . Zeller, B. (2014). Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML. Blood, 124(21).
Open this publication in new window or tab >>Anthracycline Type during Induction Associated with Outcome in Pediatric t(8;21) and Inv(16) AML
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal, Meeting abstract (Other academic) Published
National Category
Pediatrics
Identifiers
urn:nbn:se:umu:diva-101420 (URN)000349242703110 ()
Available from: 2015-04-07 Created: 2015-03-30 Last updated: 2017-12-04Bibliographically approved
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