Samuel w. Brady, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Kathryn G. Roberts, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Zhaohui Gu, Department of Computational and Quantitative Medicine & Systems Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
Lei Shi, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Stanley Pounds, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Deqing Pei, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Cheng Cheng, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Yunfeng Dai, Department of Biostatistics, University of Florida, Gainesville, FL, USA
Meenakshi Devidas, Department of Global Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA
Chunxu Qu, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Ashley N. Hill, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Debbie Payne-Turner, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Xiaotu Ma, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Ilaria Iacobucci, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Pradyuamna Baviskar, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Lei Wei, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Sasi Arunachalam, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Kohei Hagiwara, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Yanling Liu, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Diane A Flasch, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Yu Liu, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Matthew Parker, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Xiaolong Chen, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Abdelrahman H. Elsayed, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA, Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, USA
Omkar Pathak, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Yongjin Li, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Yiping Fan, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
J Robert Michael, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Michael Rusch, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Mark R. Wilkinson, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Scott Foy, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Dale J. Hedges, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Scott Newman, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Xin Zhou, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Jian Wang, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Colleen Reilly, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Edgar Sioson, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Stephen V. Rice, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Victor Pastor Loyola, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
Gang Wu, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
Evadnie Rampersaud, Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA
Shalini C. Reshmi, Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA
Julie Gastier-Foster, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Jaime M. Guidry Auvil, Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA,Office of Data Sharing, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Patee Gesuwan, Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Malcolm A. Smith, Cancer Therapeutics Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Naomi Winick, Department of Pediatric Hematology Oncology and Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
Andrew J. Carroll, Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
Nyla A. Heerema, The Ohio State University, Columbus, OH, USA
Richard C. Harvey, Department of Pathology, University of New Mexico Cancer Center, Albuquerque, NM, USA
Cheryl L. Willman, Mayo Clinical Comprehensive Cancer Center, Rochester, MN, USA
Eric Larsen, Department of Pediatrics, Maine Children's Cancer Program, Scarborough, ME, USA
Elizabeth A. Raetz, Department of Pediatrics and Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA
Michael J. Borowitz, Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
Brent L. Wood, Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA
William L. Carroll, Department of Pediatrics and Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA
Patrick A. Zweidler-McKay, ImmunoGen, Inc., Waltham, MA, USA
Karen R. Rabin, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
Leonard A. Mattano, HARP Pharma Consulting, Mystic, CT, USA
Kelly W. Maloney, Department of Pediatrics and Children's Hospital Colorado, University of Colorado, Aurora, CO, USA
Stuart S. Winter, Children's Minnesota Research Institute and Cancer and Blood Disorders Program, Minneapolis, MN, USA
Michael J. Burke, Division of Pediatric Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
Wanda Salzer, Uniformed Services University, School of Medicine, Bethesda, MD, USA
Kimberly P. Dunsmore, Department of Pediatrics, University of Virginia, Charlottesville, VA, USA
Anne L. Angiolillo, Children's National Medical Center, Washington, DC, USA
Kristine R. Crews, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
James R. Downing, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA
Sima Jeha, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
Ching-Hon Pui, Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
William E. Evans, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
Jun Yang, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
Mary V. Relling, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA
Daniela S. Gerhard, Office of Cancer Genomics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Mignon L. Loh, Department of Pediatrics, Benioff Children's Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA
Stephen P. Hunger, Department of Pediatrics and the Center for Childhood Cancer Research, Children's Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. Hungers@chop.edu
Jinghui Zhang, Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA. jinghui.zhang@stjude.org
Charles G. Mullighan, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA. charles.mullighan@stjude.org

Document Type

Article

Publication Date

9-1-2022

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.

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