Cancer Treatment Exerts Selective Pressure on Premalignant Clones

Although many driver mutations that promote cancer have been discovered, much remains to be understood about the mutational landscape that characterizes cells just prior to malignant transformation and during early oncogenesis. The existence of clonal hematopoiesis, which may progress to myelodysplastic syndromes and ultimately overt leukemia, provides an opportunity to perform statistically well-powered prospective studies of the cancer evolutionary process in blood. Bolton and colleagues examined this in the context of therapy-related myeloid neoplasms (t-MN), beginning with prospective targeting sequencing data from 24,146 patients with cancer, with 56 primary-tumor types being represented. Thirty percent of this patient cohort exhibited clonal hematopoiesis mutations, and 5,810 such mutations were identified as putative drivers of clonal hematopoiesis. A retrospective analysis revealed that specific exposures were correlated with particular types of mutations; for example, mutations in the gene ASXL1, encoding a putative polycomb-group protein that acts as a chromatin remodeler, were more common in individuals who currently smoke or formerly smoked, and cancer treatment with radiotherapy, platinum-based drugs, or topoisomerase II inhibitors was associated with mutations in DNA-damage response (DDR) genes. Based on these findings, a prospective analysis was initiated using sequentially collected blood samples from 525 patients who had been treated with cytotoxic therapy or external beam radiation therapy over a median blood sampling time of 23 months. This showed that 74% of patients had clonal hematopoiesis at the time of first sample collection; in no case did this progress to secondary hematologic cancer over the study period. Further, the cancer treatments received exerted selective pressure favoring clones with mutations in the DDR genes such as TP53, PPM1D, and CHEK2, consistent with the retrospective findings, and these mutant clones had lower fitness in the absence of the cancer therapies. Notably, in patients who had clonal hematopoiesis mutations at first sampling, the same mutations were present at the time of t-MN diagnosis. Collectively, these findings provide a detailed genetic characterization of the evolution of blood cancers from clonal hematopoiesis.

Bolton KL, Ptashkin RN, Gao T, Braunstein L, Devlin SM, Kelly D, et al. Cancer therapy shapes the fitness landscape of clonal hematopoiesis. Nat Genet 2020;52:1219–26.

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