Synapse - Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis

Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis Journal Article

Authors:	Gao, T.; Ptashkin, R.; Bolton, K. L.; Sirenko, M.; Fong, C.; Spitzer, B.; Menghrajani, K.; Arango Ossa, J. E.; Zhou, Y.; Bernard, E.; Levine, M.; Medina Martinez, J. S.; Zhang, Y.; Franch-Expósito, S.; Patel, M.; Braunstein, L. Z.; Kelly, D.; Yabe, M.; Benayed, R.; Caltabellotta, N. M.; Philip, J.; Paraiso, E.; Mantha, S.; Solit, D. B.; Diaz, L. A. Jr; Berger, M. F.; Klimek, V.; Levine, R. L.; Zehir, A.; Devlin, S. M.; Papaemmanuil, E.
Article Title:	Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis
Abstract:	Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7–22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6–33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms. © 2021, The Author(s).
Keywords:	mutation; genetic analysis; chromosome; gene expression; genotype; risk factor; physiological response; cell component; cancer
Journal Title:	Nature Communications
Volume:	12
ISSN:	2041-1723
Publisher:	Nature Publishing Group
Date Published:	2021-01-12
Start Page:	338
Language:	English
DOI:	10.1038/s41467-020-20565-7
PROVIDER:	scopus
PMCID:	PMC7804935
PUBMED:	33436578
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85099262815&doi=10.1038%2fs41467-020-20565-7&partnerID=40&md5=12d1a6db8e19b12c9f736550ab1321d6
Notes:	Article -- Export Date: 1 February 2021 -- Source: Scopus