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

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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

Date: 2021
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DOI: 10.1038/s41467-020-20565-7

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