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Forestier, Erik
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Publications (10 of 77) Show all publications
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, article id 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, article id 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
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, p. 118-128Article 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, p. 70-77Article 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, p. 1015-1021Article 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
Lundin, C., Forestier, E., Andersen, M. K., Autio, K., Barbany, G., Cavelier, L., . . . Johansson, B. (2014). Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries. Journal of Hematology & Oncology, 7, 32
Open this publication in new window or tab >>Clinical and genetic features of pediatric acute lymphoblastic leukemia in Down syndrome in the Nordic countries
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2014 (English)In: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 7, p. 32-Article in journal (Refereed) Published
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.

Keyword
Down syndrome, ALL, Children, Clinical features, Genetic features, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-90790 (URN)10.1186/1756-8722-7-32 (DOI)000336058600001 ()24726034 (PubMedID)
Available from: 2014-10-09 Created: 2014-07-01 Last updated: 2017-12-05Bibliographically approved
Levinsen, M., Taskinen, M., Abrahamsson, J., Forestier, E., Frandsen, T. L., Harila-Saari, A., . . . Schmiegelow, K. (2014). Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia. Pediatric Blood & Cancer, 61(8), 1416-1421
Open this publication in new window or tab >>Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia
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2014 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, no 8, p. 1416-1421Article in journal (Refereed) Published
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.

Keyword
ALL, chemotherapy, minimal residual disease
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-91182 (URN)10.1002/pbc.24981 (DOI)000337698600016 ()
Available from: 2014-07-23 Created: 2014-07-21 Last updated: 2017-12-05Bibliographically approved
Olsson, L., Castor, A., Behrendtz, M., Biloglav, A., Forestier, E., Paulsson, K. & Johansson, B. (2014). Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011. Leukemia, 28(2), 302-310
Open this publication in new window or tab >>Deletions of IKZF1 and SPRED1 are associated with poor prognosis in a population-based series of pediatric B-cell precursor acute lymphoblastic leukemia diagnosed between 1992 and 2011
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2014 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 2, p. 302-310Article in journal (Refereed) Published
Abstract [en]

Despite the favorable prognosis of childhood acute lymphoblastic leukemia (ALL), a substantial subset of patients relapses. As this occurs not only in the high risk but also in the standard/intermediate groups, the presently used risk stratification is suboptimal. The underlying mechanisms for treatment failure include the presence of genetic changes causing insensitivity to the therapy administered. To identify relapse-associated aberrations, we performed single-nucleotide polymorphism array analyses of 307 uniformly treated, consecutive pediatric ALL cases accrued during 1992-2011. Recurrent aberrations of 14 genes in patients who subsequently relapsed or had induction failure were detected. Of these, deletions/uniparental isodisomies of ADD3, ATP10A, EBF1, IKZF1, PAN3, RAG1, SPRED1 and TBL1XR1 were significantly more common in B-cell precursor ALL patients who relapsed compared with those remaining in complete remission. In univariate analyses, age (>= 10 years), white blood cell counts (>100 x 10(9)/l), t(9; 22)(q34; q11), MLL rearrangements, near-haploidy and deletions of ATP10A, IKZF1, SPRED1 and the pseudoautosomal 1 regions on Xp/Yp were significantly associated with decreased 10-year event-free survival, with IKZF1 abnormalities being an independent risk factor in multivariate analysis irrespective of the risk group. Older age and deletions of IKZF1 and SPRED1 were also associated with poor overall survival. Thus, analyses of these genes provide clinically important information.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-87176 (URN)10.1038/leu.2013.206 (DOI)000331223900009 ()
Available from: 2014-03-31 Created: 2014-03-24 Last updated: 2017-12-05Bibliographically approved
Zachariadis, V., Schoumans, J., Ofverholm, I., Barbany, G., Halvardsson, E., Forestier, E., . . . Nordgren, A. (2014). Detecting dic(9;20)(p13.2;p11.2)-positive B-cell precursor acute lymphoblastic leukemia in a clinical setting using fluorescence in situ hybridization [Letter to the editor]. Leukemia, 28(1), 196-198
Open this publication in new window or tab >>Detecting dic(9;20)(p13.2;p11.2)-positive B-cell precursor acute lymphoblastic leukemia in a clinical setting using fluorescence in situ hybridization
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2014 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 28, no 1, p. 196-198Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Nature Publishing Group, 2014
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:umu:diva-85786 (URN)10.1038/leu.2013.189 (DOI)000329441200024 ()
Available from: 2014-02-13 Created: 2014-02-10 Last updated: 2017-12-06Bibliographically approved
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