TY - JOUR
T1 - Interplay between chromosomal alterations and gene mutations shapes the evolutionary trajectory of clonal hematopoiesis
AU - Gao, Teng
AU - Ptashkin, Ryan
AU - Bolton, Kelly L.
AU - Sirenko, Maria
AU - Fong, Christopher
AU - Spitzer, Barbara
AU - Menghrajani, Kamal
AU - Ossa, Juan E.Arango
AU - Zhou, Yangyu
AU - Bernard, Elsa
AU - Levine, Max
AU - Martinez, Juan S.Medina
AU - Zhang, Yanming
AU - Franch-Expósito, Sebastià
AU - Patel, Minal
AU - Braunstein, Lior Z.
AU - Kelly, Daniel
AU - Yabe, Mariko
AU - Benayed, Ryma
AU - Caltabellotta, Nicole M.
AU - Philip, John
AU - Paraiso, Ederlinda
AU - Mantha, Simon
AU - Solit, David B.
AU - Diaz, Luis A.
AU - Berger, Michael F.
AU - Klimek, Virginia
AU - Levine, Ross L.
AU - Zehir, Ahmet
AU - Devlin, Sean M.
AU - Papaemmanuil, Elli
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099262815&partnerID=8YFLogxK
U2 - 10.1038/s41467-020-20565-7
DO - 10.1038/s41467-020-20565-7
M3 - Article
C2 - 33436578
AN - SCOPUS:85099262815
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 338
ER -