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Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Bolton, Kelly L 
Ptashkin, Ryan N 
Gao, Teng 
Braunstein, Lior 
Devlin, Sean M 

Abstract

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.

Description

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Cell Transformation, Neoplastic, Child, Child, Preschool, Clonal Evolution, Clonal Hematopoiesis, Cohort Studies, Female, Genetic Fitness, Humans, Infant, Infant, Newborn, Leukemia, Myeloid, Male, Middle Aged, Models, Biological, Mutation, Neoplasms, Neoplasms, Second Primary, Selection, Genetic, Young Adult

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

52

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved