Beyond hematologic malignancies: Clonal hematopoiesis of indeterminate potential and the risk of solid tumors in the UK biobank.

Abstract

10502 Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in hematopoietic stem cells. While CHIP is associated with hematologic malignancies, its relationship with solid tumors remains incompletely characterized. We conducted a comprehensive analysis of CHIP and cancer risk in a large population-based cohort. Methods: We analyzed 409,150 UK Biobank participants with whole exome sequencing, including 13,709 (3.4%) with CHIP. CHIP was defined as somatic mutations in myeloid driver genes at variant allele frequency (VAF) ≥2%. Incident cancers were ascertained through registry linkage over median 15.5-year follow-up. We performed propensity score-matched Cox regression adjusting for age, sex, ethnicity, smoking, BMI, diabetes, chronic kidney disease, and family history. Gene-specific, VAF-stratified, and multi-hit analyses were conducted. Results: Among 77,695 incident cancers, CHIP was associated with increased risk of any cancer (HR 1.22, 95% CI 1.18-1.27), including both hematologic and solid tumors. Associations were strongest for myeloid neoplasms (HR 10.49, 95% CI 8.64-12.74), including AML (HR 11.09), MDS (HR 9.75), and MPN (HR 8.03). For solid tumors, significant associations were observed for lung cancer (HR 1.50, 95% CI 1.31-1.73), particularly adenocarcinoma (HR 1.79, 95% CI 1.48-2.16), and esophageal cancer (HR 1.52, 95% CI 1.13-2.03). Notably, esophageal squamous cell carcinoma showed particularly elevated risk (HR 2.28, 95% CI 1.37-3.81). VAF-stratified analyses revealed dose-response for esophageal cancer: large clones (defined as VAF ≥20%) conferred HR 2.23 (95% CI 1.32-3.75) and very large clones (defined as VAF ≥30%) HR 2.72 (95% CI 1.39-5.30). Multi-hit CHIP (≥2 mutations) was associated with HR 3.35 (95% CI 1.46-7.71) for esophageal cancer and HR 4.07 (95% CI 1.79-9.21) for esophageal adenocarcinoma. Gene-specific analyses showed TET2 mutations increased esophageal adenocarcinoma risk (HR 2.46, 95% CI 1.21-5.03). Results remained consistent in 5-year landmark analyses. Conclusions: CHIP is associated with significantly increased risk of both hematologic and select solid malignancies. We identify esophageal cancer, particularly squamous cell carcinoma, as a novel CHIP-associated malignancy with clear dose-response by clone burden. These findings warrant external validation and, if confirmed, suggest CHIP features may help refine risk stratification strategies for selected solid tumors.