Clonal Hematopoiesis and Incident Solid Cancers Resolved by Histologic Subtype: A Prospective Cohort Study

Clonal hematopoiesis of indeterminate potential (CHIP) is a recognized precursor of myeloid malignancy and an independent cardiovascular risk factor, but its relationship with solid tumors is incompletely defined, particularly at histologic resolution. Here, we quantify the association between CHIP and incident cancer across hematologic and solid-organ sites, by clone size, mutation number, and histologic subtype in a prospective cohort of UK Biobank participants with baseline genetic sequencing and cancer ascertained by national registry linkage; those with pre-baseline cancer were excluded. Vanderbilt BioVU was used for replication. CHIP was associated with any incident cancer (HR, 1.22; 95% CI, 1.18-1.27) and with all solid tumors combined (HR, 1.13; 95% CI, 1.08-1.19). Among 17 endpoints, two survived multiple testing correction: lung adenocarcinoma (HR, 1.79; 95% CI, 1.48 - 2.16) and esophageal squamous cell carcinoma (HR, 2.28; 95% CI, 1.37-3.81). Risk increased with clone size and multi-hit CHIP, most markedly for esophageal cancer (VAF ≥30%: HR, 2.72), and the esophageal squamous association persisted in 5-year landmark analysis (HR, 2.57). In BioVU, CHIP was directionally associated with esophageal cancer and lung adenocarcinoma and its association with all solid tumors overall (HR, 1.24; 95% CI, 1.17-1.32) was confirmed. These findings extend CHIP from a hematologic and cardiovascular risk marker to a risk marker of solid-organ cancer risk with histologic resolution and motivate clone-size aware risk models and mechanistic studies.