High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event

Paulsson, Kajsa

doi:10.1080/23723556.2015.1064555

Cited by 9 publications

(11 citation statements)

References 10 publications

(14 reference statements)

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“…Biologically and clinically significant whole chromosomal phenotypes are a notable feature of childhood malignancies other than medulloblastoma. Characteristic patterns of non-random whole chromosomal aberrations in neuroblastoma (so-called whole-chromosomal changes phenotype; more than two whole chromosomal aberrations) 25 , 26 and high hyperdiploid acute lymphoblastic leukaemia (so-called high-hyperdiploidy phenotype [HeH]; 51–65 chromosomes) 27 define tumour subgroups with favourable prognoses. Additionally, choroid plexus papillomas and adult infratentorial ependymomas (posterior fossa ependymoma type B) are characterised by multiple whole chromosomal abberations.…”

Section: Discussionmentioning

confidence: 99%

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial

Goschzik

Schwalbe

Hicks

et al. 2018

The Lancet Oncology

105

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SummaryBackgroundMost children with medulloblastoma fall within the standard-risk clinical disease group defined by absence of high-risk features (metastatic disease, large-cell/anaplastic histology, and MYC amplification), which includes 50–60% of patients and has a 5-year event-free survival of 75–85%. Within standard-risk medulloblastoma, patients in the WNT subgroup are established as having a favourable prognosis; however, outcome prediction for the remaining majority of patients is imprecise. We sought to identify novel prognostic biomarkers to enable improved risk-adapted therapies.MethodsThe HIT-SIOP PNET 4 trial recruited 338 patients aged 4–21 years with medulloblastoma between Jan 1, 2001, and Dec 31, 2006, in 120 treatment institutions in seven European countries to investigate hyperfractionated radiotherapy versus standard radiotherapy. In this retrospective analysis, we assessed the remaining tumour samples from patients in the HIT-SIOP PNET 4 trial (n=136). We assessed the clinical behaviour of the molecularly defined WNT and SHH subgroups, and identified novel independent prognostic markers and models for standard-risk patients with non-WNT/non-SHH disease. Because of the scarcity and low quality of available genomic material, we used a mass spectrometry-minimal methylation classifier assay (MS-MIMIC) to assess methylation subgroup and a molecular inversion probe array to detect genome-wide copy number aberrations. Prognostic biomarkers and models identified were validated in an independent, demographically matched cohort (n=70) of medulloblastoma patients with non-WNT/non-SHH standard-risk disease treated with conventional therapies (maximal surgical resection followed by adjuvant craniospinal irradiation [all patients] and chemotherapy [65 of 70 patients], at UK Children's Cancer and Leukaemia Group and European Society for Paediatric Oncology (SIOPE) associated treatment centres between 1990 and 2014. These samples were analysed by Illumina 450k DNA methylation microarray. HIT-SIOP PNET 4 is registered with ClinicalTrials.gov, number NCT01351870.FindingsWe analysed methylation subgroup, genome-wide copy number aberrations, and mutational features in 136 assessable tumour samples from the HIT-SIOP PNET 4 cohort, representing 40% of the 338 patients in the trial cohort. This cohort of 136 samples consisted of 28 (21%) classified as WNT, 17 (13%) as SHH, and 91 (67%) as non-WNT/non-SHH (we considered Group3 and Group4 medulloblastoma together in our analysis because of their similar molecular and clinical features). Favourable outcomes for WNT tumours were confirmed in patients younger than 16 years, and all relapse events in SHH (four [24%] of 17) occurred in patients with TP53 mutation (TP53mut) or chromosome 17p loss. A novel whole chromosomal aberration signature associated with increased ploidy and multiple non-random whole chromosomal aberrations was identified in 38 (42%) of the 91 samples from patients with non-WNT/non-SHH medulloblastoma in the HIT-SIOP PNET 4 cohort. Biomarkers associate...

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Section: Discussionmentioning

confidence: 99%

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial

Goschzik

Schwalbe

Hicks

et al. 2018

The Lancet Oncology

105

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“…iAMP21 is characterized by a rearranged chromosome 21 patterned with amplified and deleted genomic regions [127,128]. As in DS-ALL, there is a high incidence of genetic alterations affecting signaling effectors (NRAS, KRAS, FLT3, and SH2B3) in HeH and iAMP21 subtypes [129][130][131]. However, the molecular bases of this possible oncogenic cooperation are currently unknown.…”

Section: Gain Of Chromosome 21 In Pediatric B-allmentioning

confidence: 99%

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

2020

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Structural and numerical alterations of chromosome 21 are extremely common in hematological malignancies. While the functional impact of chimeric transcripts from fused chromosome 21 genes such as TEL-AML1, AML1-ETO, or FUS-ERG have been extensively studied, the role of gain of chromosome 21 remains largely unknown. Gain of chromosome 21 is a frequently occurring aberration in several types of acute leukemia and can be found in up to 35% of cases. Children with Down syndrome (DS), who harbor constitutive trisomy 21, highlight the link between gain of chromosome 21 and leukemogenesis, with an increased risk of developing acute leukemia compared with other children. Clinical outcomes for DS-associated leukemia have improved over the years through the development of uniform treatment protocols facilitated by international cooperative groups. The genetic landscape has also recently been characterized, providing an insight into the molecular pathogenesis underlying DS-associated leukemia. These studies emphasize the key role of trisomy 21 in priming a developmental stage and cellular context susceptible to transformation, and have unveiled its cooperative function with additional genetic events that occur during leukemia progression. Here, using DS-leukemia as a paradigm, we aim to integrate our current understanding of the role of trisomy 21, of critical dosage-sensitive chromosome 21 genes, and of associated mechanisms underlying the development of hematological malignancies. This review will pave the way for future investigations on the broad impact of gain of chromosome 21 in hematological cancer, with a view to discovering new vulnerabilities and develop novel targeted therapies to improve long term outcomes for DS and non-DS patients.

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“…Molecular genomic abnormalities, or genetic events that occur at subchromosomal levels, are detected by gene sequencing or gene expression patterns and have also been characterized for childhood ALL (28,51). Most recently, the Philadelphia-like subtype (Ph þ -like, BCR-ABL1-like) B-ALL has been identified by gene expression patterns similar to that found in BCR-ABL1positive B-ALL and has been further shown to have mutations affecting genes important in leukemogenesis such as IKZF1 (52) and CDKN2A/B (31).…”

Section: Molecular Genomic Abnormalitiesmentioning

confidence: 99%

Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype

Williams

Yang

Hirsch

et al. 2019

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Although substantial advances in the identification of cytogenomic subtypes of childhood acute lymphoblastic leukemia (ALL) have been made in recent decades, epidemiologic research characterizing the etiologic heterogeneity of ALL by subtype has not kept pace. The purpose of this review is to summarize the current literature concerning subtype-specific epidemiologic risk factor associations with ALL subtype defined by immunophenotype (e.g., B-cell vs. T-cell) and cytogenomics (including gross chromosomal events characterized by recurring numerical and structural abnormalities, along with cryptic balanced rearrangements, and focal gene deletions). In case-control analyses investigating nongenetic risk factors, home paint exposure is associated with hyperdi-ploid, MLL-rearranged, and ETV6-RUNX1 subtypes, yet there are few differences in risk factor associations between T-and B-ALL. Although the association between maternal smoking and ALL overall has been null, maternal smoking is associated with an increasing number of gene deletions among cases. GWAS-identified variants in ARID5B have been the most extensively studied and are strongly associated with hyperdiploid B-ALL. GATA3 single nucleotide variant rs3824662 shows a strong association with Ph-like ALL (OR ¼ 3.14). However, there have been relatively few population-based studies of adequate sample size to uncover risk factors that may define etiologic heterogeneity between and within the currently defined cytogenomic ALL subtypes.

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High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event

Cited by 9 publications

References 10 publications

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial

Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

Is There Etiologic Heterogeneity between Subtypes of Childhood Acute Lymphoblastic Leukemia? A Review of Variation in Risk by Subtype

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