Associations Between Cancer Predisposition Mutations and Clonal Hematopoiesis in Patients With Solid Tumors.

Abstract

Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors. We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants. We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in <i>ATM</i> and CH. Germline and CH comutation patterns in <i>ATM</i>, <i>TP53</i>, and <i>CHEK2</i> suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH-<i>PPM1D</i> mutations, similar to somatic tumor-associated <i>PPM1D</i> mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes <i>ATM</i>, <i>CHEK2</i>, and <i>TP53</i>. Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in <i>TP53</i> were identified as an independent risk factor (hazard ratio, 36; <i>P</i> < .001) for secondary leukemias. Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.