The genomic landscape of pediatric acute lymphoblastic leukemia

Samuel W. Brady, Kathryn G. Roberts, Zhaohui Gu, Lei Shi, Stanley Pounds, Deqing Pei, Cheng Cheng, Yunfeng Dai, Meenakshi Devidas, Chunxu Qu, Ashley N. Hill, Debbie Payne-Turner, Xiaotu Ma, Ilaria Iacobucci, Pradyuamna Baviskar, Lei Wei, Sasi Arunachalam, Kohei Hagiwara, Yanling Liu, Diane A. FlaschYu Liu, Matthew Parker, Xiaolong Chen, Abdelrahman H. Elsayed, Omkar Pathak, Yongjin Li, Yiping Fan, J. Robert Michael, Michael Rusch, Mark R. Wilkinson, Scott Foy, Dale J. Hedges, Scott Newman, Xin Zhou, Jian Wang, Colleen Reilly, Edgar Sioson, Stephen V. Rice, Victor Pastor Loyola, Gang Wu, Evadnie Rampersaud, Shalini C. Reshmi, Julie Gastier-Foster, Jaime M. Guidry Auvil, Patee Gesuwan, Malcolm A. Smith, Naomi Winick, Andrew J. Carroll, Nyla A. Heerema, Richard C. Harvey, Cheryl L. Willman, Eric Larsen, Elizabeth A. Raetz, Michael J. Borowitz, Brent L. Wood, William L. Carroll, Patrick A. Zweidler-McKay, Karen R. Rabin, Leonard A. Mattano, Kelly W. Maloney, Stuart S. Winter, Michael J. Burke, Wanda Salzer, Kimberly P. Dunsmore, Anne L. Angiolillo, Kristine R. Crews, James R. Downing, Sima Jeha, Ching Hon Pui, William E. Evans, Jun J. Yang, Mary V. Relling, Daniela S. Gerhard, Mignon L. Loh, Stephen P. Hunger, Jinghui Zhang, Charles G. Mullighan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1376-1389
Number of pages14
JournalNature genetics
Volume54
Issue number9
DOIs
StatePublished - Sep 2022
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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