期刊
NATURE GENETICS
卷 52, 期 11, 页码 1219-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-00710-0
关键词
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资金
- National Institutes of Health [K08 CA241318, K12 CA120780, P50 CA172012, UG1 HL069315]
- American Society of Hematology
- EvansMDS Foundation
- European Hematology Association
- Gabrielle's Angels Foundation
- V Foundation
- Geoffrey Beene Foundation
- UNC Oncology Clinical Translational Research Training Program
- Cycle for Survival
- Starr Cancer Consortium
- Cancer Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]
- Conquer Cancer Foundation Young Investigator Award
- Prostate Cancer Foundation Young Investigator Award
- Defense Early Investigator Research Award [W81XWH-18-1-0330]
- Prostate Cancer Foundation Challenge Award
- Intramural Research Program of the National Cancer Institute, National Institutes of Health
- Cancer Center Support Grant [P30 CA008748]
- Tissue Core and Genomic Core Facilities at the H. Lee Moffitt Cancer Center & Research Institute, an NCI-designated Comprehensive Cancer Center [P30 CA076292]
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. Environmental exposures shape patterns of selection for mutations in clonal hematopoiesis. Cancer therapies promote the growth of clones with mutations that are strongly enriched in treatment-related myeloid neoplasms.
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