Large-scale Identification of Clonal Hematopoiesis and Mutations Recurrent in Blood Cancers

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations usable for CHIP detection by performing a data mining analysis of 48 somatic mutation landscape studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with leukemia or other hematologic malignancy. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole-exome sequencing data from 4,538 persons belonging to three noncancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and precancer surveillance for both children and adults.