Cancer therapy shapes the fitness landscape of clonal hematopoiesis

Acquired mutations are pervasive across normal tissues. However, our 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 (tMN). We find 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 (DDR) genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DDR clones outcompete other clones when exposed to certain therapies. Among cases where 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.