Cost-Effective and Scalable Clonal Hematopoiesis Assay Provides Insight into Clonal Dynamics

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related phenomenon that occurs when hematopoietic stem cells acquire mutations in a select set of genes commonly mutated in myeloid neoplasia which then expand clonally. Current sequencing assays to detect CHIP mutations are not optimized for the detection of these variants and can be cost-prohibitive when applied to large cohorts or serial sequencing. In this study, an affordable (∼$8 per sample), accurate, and scalable sequencing assay for CHIP is introduced and validated. The efficacy of the assay is demonstrated by identifying CHIP mutations in a cohort of 456 individuals with DNA collected at multiple timepoints in the Vanderbilt BioVU biobank and quantifying clonal expansion rates over time. A total of 101 individuals with CHIP/CCUS were identified, and individual-level clonal expansion rate was calculated using the variant allele fraction (VAF) at both timepoints. Differences in clonal expansion rate by driver gene were observed, but there was also significant individual-level heterogeneity, emphasizing the multifactorial nature of clonal expansion. Additionally, the study explores mutation co-occurrence and clonal competition between multiple driver mutations.