Dataset Information

The genomic landscape of pediatric acute lymphoblastic leukemia.

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

SUBMITTER: Brady SW

PROVIDER: S-EPMC9700506 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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The genomic landscape of pediatric acute lymphoblastic leukemia.

Brady Samuel W SW Roberts Kathryn G KG Gu Zhaohui Z Shi Lei L Pounds Stanley S Pei Deqing D Cheng Cheng C Dai Yunfeng Y Devidas Meenakshi M Qu Chunxu C Hill Ashley N AN Payne-Turner Debbie D Ma Xiaotu X Iacobucci Ilaria I Baviskar Pradyuamna P Wei Lei L Arunachalam Sasi S Hagiwara Kohei K Liu Yanling Y Flasch Diane A DA Liu Yu Y Parker Matthew M Chen Xiaolong X Elsayed Abdelrahman H AH Pathak Omkar O Li Yongjin Y Fan Yiping Y Michael J Robert JR Rusch Michael M Wilkinson Mark R MR Foy Scott S Hedges Dale J DJ Newman Scott S Zhou Xin X Wang Jian J Reilly Colleen C Sioson Edgar E Rice Stephen V SV Pastor Loyola Victor V Wu Gang G Rampersaud Evadnie E Reshmi Shalini C SC Gastier-Foster Julie J Guidry Auvil Jaime M JM Gesuwan Patee P Smith Malcolm A MA Winick Naomi N Carroll Andrew J AJ Heerema Nyla A NA Harvey Richard C RC Willman Cheryl L CL Larsen Eric E Raetz Elizabeth A EA Borowitz Michael J MJ Wood Brent L BL Carroll William L WL Zweidler-McKay Patrick A PA Rabin Karen R KR Mattano Leonard A LA Maloney Kelly W KW Winter Stuart S SS Burke Michael J MJ Salzer Wanda W Dunsmore Kimberly P KP Angiolillo Anne L AL Crews Kristine R KR Downing James R JR Jeha Sima S Pui Ching-Hon CH Evans William E WE Yang Jun J JJ Relling Mary V MV Gerhard Daniela S DS Loh Mignon L ML Hunger Stephen P SP Zhang Jinghui J Mullighan Charles G CG

Nature genetics 20220901 9

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated ...[more]

PMID: 36050548

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Project description:Differences in survival have been reported between pediatric and adult acute lymphoblastic leukemia. The inferior prognosis in adult acute lymphoblastic leukemia is not fully understood but could be attributed, in part, to differences in genomic alterations found in adult as compared to in pediatric acute lymphoblastic leukemia.We compared two different sets of high-density single nucleotide polymorphism array genotyping data from 75 new diagnostic adult and 399 previously published diagnostic pediatric acute lymphoblastic leukemia samples. The patients' samples were randomly acquired from among Caucasian and Asian populations and hybridized to either Affymetrix 50K or 250K single nucleotide polymorphism arrays. The array data were investigated with Copy Number Analysis for GeneChips (CNAG) software for allele-specific copy number analysis.The high density single nucleotide polymorphism array analysis of 75 samples of adult acute lymphoblastic leukemia led to the identification of numerous cryptic and submicroscopic genomic lesions with a mean of 7.6 genomic alterations per sample. The patterns and frequencies of lesions detected in the adult samples largely reproduced known genomic hallmarks detected in previous single nucleotide polymorphism-array studies of pediatric acute lymphoblastic leukemia, such as common deletions of 3p14.2 (FHIT), 5q33.3 (EBF), 6q, 9p21.3 (CDKN2A/B), 9p13.2 (PAX5), 13q14.2 (RB1) and 17q11.2 (NF1). Some differences between adult and pediatric acute lymphoblastic leukemia were identified when the pediatric data set was partitioned into hyperdiploid and non-hyperdiploid cases and then compared to the nearly exclusively non-hyperdiploid adult samples. In this analysis, adult samples had a higher rate of deletions of chromosome 17p (TP53) and duplication of 17q.Our analysis of adult acute lymphoblastic leukemia cases led to the identification of new potential target lesions relevant for the pathogenesis of acute lymphoblastic leukemia. However, no unequivocal pattern of submicroscopic genomic alterations was found to separate adult acute lymphoblastic leukemia from pediatric acute lymphoblastic leukemia. Therefore, apart from different therapy regimen, differences of prognosis between adult and pediatric acute lymphoblastic leukemia are probably based on genetic subgroups according to cytogenetically detectable lesions but not focal genomic copy number microlesions.

Dataset Information

The genomic landscape of pediatric acute lymphoblastic leukemia.

Publications

The genomic landscape of pediatric acute lymphoblastic leukemia.

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