The genomic landscape of pediatric acute lymphoblastic leukemia

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...

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Published in:Nature genetics Vol. 54; no. 9; pp. 1376 - 1389
Main Authors: Brady, Samuel W., Roberts, Kathryn G., Gu, Zhaohui, Shi, Lei, Pounds, Stanley, Pei, Deqing, Cheng, Cheng, Dai, Yunfeng, Devidas, Meenakshi, Qu, Chunxu, Hill, Ashley N., Payne-Turner, Debbie, Ma, Xiaotu, Iacobucci, Ilaria, Baviskar, Pradyuamna, Wei, Lei, Arunachalam, Sasi, Hagiwara, Kohei, Liu, Yanling, Flasch, Diane A., Liu, Yu, Parker, Matthew, Chen, Xiaolong, Elsayed, Abdelrahman H., Pathak, Omkar, Li, Yongjin, Fan, Yiping, Michael, J. Robert, Rusch, Michael, Wilkinson, Mark R., Foy, Scott, Hedges, Dale J., Newman, Scott, Zhou, Xin, Wang, Jian, Reilly, Colleen, Sioson, Edgar, Rice, Stephen V., Pastor Loyola, Victor, Wu, Gang, Rampersaud, Evadnie, Reshmi, Shalini C., Gastier-Foster, Julie, Guidry Auvil, Jaime M., Gesuwan, Patee, Smith, Malcolm A., Winick, Naomi, Carroll, Andrew J., Heerema, Nyla A., Harvey, Richard C., Willman, Cheryl L., Larsen, Eric, Raetz, Elizabeth A., Borowitz, Michael J., Wood, Brent L., Carroll, William L., Zweidler-McKay, Patrick A., Rabin, Karen R., Mattano, Leonard A., Maloney, Kelly W., Winter, Stuart S., Burke, Michael J., Salzer, Wanda, Dunsmore, Kimberly P., Angiolillo, Anne L., Crews, Kristine R., Downing, James R., Jeha, Sima, Pui, Ching-Hon, Evans, William E., Yang, Jun J., Relling, Mary V., Gerhard, Daniela S., Loh, Mignon L., Hunger, Stephen P., Zhang, Jinghui, Mullighan, Charles G.
Format: Journal Article
Language:English
Published: New York Nature Publishing Group US 01.09.2022
Nature Publishing Group
Subjects:
631/67/1990/283/2125
692/699/67/1990/283/2125
Acute lymphoblastic leukemia
Age
Agriculture
Animal Genetics and Genomics
Biomedical and Life Sciences
Biomedicine
Cancer
Cancer Research
Child
Children
Chromosome Aberrations
Chromosomes
Evolution
Exome - genetics
Gene Function
Genes
Genomes
Genomics
Human Genetics
Humans
Leukemia
Mutation
Pediatrics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Subgroups
SUMO protein
Transcriptomes
Ubiquitination
ISSN:1061-4036, 1546-1718, 1546-1718
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Summary: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. A genomic and transcriptomic analysis of 2,754 childhood acute lymphoblastic leukemias identifies 376 putative driver genes, and associations between disease subtypes and prognosis.
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Contribution: S.W.B. genomic data analysis, data interpretation and manuscript writing. K.G.R. study design, sample preparation, data interpretation and manuscript writing. Z.G., L.S., S.P., C.Q., X.M., L.W., S.A., K.H., Y.L., B.X., D.A.F., O.P., C.R., Y.L., M.P., X.C., Y.L., Y.F., J.R.M., M.R., M.R.W., S.F., D.H., S.Ne, X.Z., J.W., E.S., S.R., V.P., G.W., A.E., and E.R., data analysis. D.P. and C.C., statistical analysis. A.N.H. and D.P-T., sample preparation. I.I. and P.B., sample preparation and experimental work. M.J.B. and B.L.W. reviewed flow cytometry. Y.D., M.D., S.C.R., J.G-F., J. G-A., P.G., M.A.S., N.W., A.J.C., N.A.H., R.C.H., C.L.W., E.L., E.A.R., W.L.C., P.A.Z-M., K.R.R., L.A.M., K.W.M., S.S.W., M.J.B., W.S., K.P.D., A.A., K.C., J.R.D., S.J., C-H.P., W.E.E., J.Y., M.V.R., D.S.G., M.L.L., and S.P.H., patient samples and clinical data. J.Z. data interpretation and manuscript writing. C.G.M. designed and oversaw the study, data interpretation and manuscript writing.
These authors jointly supervised this work
These authors contributed equally.
Deceased
Authorship contribution
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-022-01159-z