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Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

ABSTRACT: There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P?=?2.11?×?10-8), for high-hyperdiploid ALL at 5q31.1 (rs886285, P?=?1.56?×?10-8) and 6p21.31 (rs210143 in BAK1, P?=?2.21?×?10-8), and ETV6-RUNX1 ALL at 17q21.32 (rs10853104 in IGF2BP1, P?=?1.82?×?10-8). Particularly notable are the pleiotropic effects of the BAK1 variant on multiple haematological malignancies and specific effects of IGF2BP1 on ETV6-RUNX1 ALL evidenced by both germline and somatic genomic analyses. Integration of GWAS signals with transcriptomic/epigenomic profiling and 3D chromatin interaction data for these leukaemia risk loci suggests deregulation of B-cell development and the cell cycle as central mechanisms governing genetic susceptibility to ALL.

SUBMITTER: Vijayakrishnan J

PROVIDER: S-EPMC6877561 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

Vijayakrishnan Jayaram J Qian Maoxiang M Studd James B JB Yang Wenjian W Kinnersley Ben B Law Philip J PJ Broderick Peter P Raetz Elizabeth A EA Allan James J Pui Ching-Hon CH Vora Ajay A Evans William E WE Moorman Anthony A Yeoh Allen A Yang Wentao W Li Chunliang C Bartram Claus R CR Mullighan Charles G CG Zimmerman Martin M Hunger Stephen P SP Schrappe Martin M Relling Mary V MV Stanulla Martin M Loh Mignon L ML Houlston Richard S RS Yang Jun J JJ

Nature communications 20191125 1

There is increasing evidence for a strong inherited genetic basis of susceptibility to acute lymphoblastic leukaemia (ALL) in children. To identify new risk variants for B-cell ALL (B-ALL) we conducted a meta-analysis with four GWAS (genome-wide association studies), totalling 5321 cases and 16,666 controls of European descent. We herein describe novel risk loci for B-ALL at 9q21.31 (rs76925697, P = 2.11 × 10<sup>-8</sup>), for high-hyperdiploid ALL at 5q31.1 (rs886285, P = 1.56 × 10<sup>-8</sup ...[more]

PMID: 31767839

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Project description:BackgroundAbout a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome.MethodsLeukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL.Findings30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial).InterpretationETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy.FundingUS National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).

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Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

Publications

Identification of four novel associations for B-cell acute lymphoblastic leukaemia risk.

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