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

Teng Gao, Ryan Ptashkin, Kelly L. Bolton, Maria Sirenko, Christopher Fong, Barbara Spitzer, Kamal Menghrajani, Juan E.Arango Ossa, Yangyu Zhou, Elsa Bernard, Max Levine, Juan S.Medina Martinez, Yanming Zhang, Sebastià Franch-Expósito, Minal Patel, Lior Z. Braunstein, Daniel Kelly, Mariko Yabe, Ryma Benayed, Nicole M. CaltabellottaJohn Philip, Ederlinda Paraiso, Simon Mantha, David B. Solit, Luis A. Diaz, Michael F. Berger, Virginia Klimek, Ross L. Levine, Ahmet Zehir, Sean M. Devlin, Elli Papaemmanuil

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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.

Original languageEnglish
Article number338
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

Fingerprint

Dive into the research topics of 'Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis'. Together they form a unique fingerprint.

Cite this