medRxiv. 2025 Mar 23. pii: 2025.03.21.25324408. [Epub ahead of print]
Somatic mosaicism (SM), the presence of somatic mutations, is classified as clonal hematopoiesis (CH) when it occurs in hematopoietic cells at an age-related rate. CH is associated with risk for hematologic malignancies and cardiovascular disease, but most studies are predominately based on individuals of European ancestry. Using peripheral blood whole exome sequencing data from 125,748 individuals of diverse genetic ancestries, we cataloged 503,703 SM mutations based on low variant allele frequency distributions and 89,361 CH variants based on age-skewing. We examined CH prevalence across ancestry groups, including commonly recognized pathogenic variants in myeloid (M-CHIP) and lymphoid (L-CHIP) malignancies. CH and M-CHIP variants had the highest prevalence in the European non-Finnish ancestry group, and males trended toward more M-CHIP variants. Ancestry differences in CH included more mutations in NF1 in African/African American, TP53 in European, and CUX1 in Asian and Latino/Admixed American ancestry groups. Linking the identified CH variants to a cancer database, CH was detected in 14% (55,190/391,102) of patient tumors. Prevalence of CH variants in some solid tumors ranged from 25% - 40%. M-CHIP variants in solid tumors were associated with younger age (61 vs 63, p <0.001), while M-CHIP in hematologic malignancies were linked to older age (60 vs 50, p <0.001), suggesting differences in disease biology. This study provides a catalog of SM, CH, and CHIP variants across diverse ancestry groups, highlighting differences that are important to inform clinical care, drug discovery, and study design to maximize generalizability across individuals.
KEY POINTS: Establish a large-scale catalog of somatic mosaicism and clonal hematopoiesis mutations across genetic ancestry groups.Mutation occurrences within clonal hematopoiesis genes vary across ancestry groups, with age, and across tumor types.