Clonal hematopoiesis mutation is associated with risk of incident lung cancer and death.

Clonal hematopoiesis (CH) has emerged as a potential risk factor with leukemia and some solid tumors, but the association between CHIP and lung cancer risk or death remains to be elucidated. This study utilized a longitudinal cohort design derived from the UK Biobank, incorporating whole-exome sequencing to identify CH mutations. The analysis included a nested 1:5 case-control of 3750 incident lung cancer cases and 18,687 controls matched on age and year at blood draw, sex, race, and smoking status. Mediation analyses were employed to explore the role of inflammatory markers and Mendelian randomization analysis to investigate the causal role of CHIP on the incidence of lung cancer. The analysis revealed a significant association between CH mutations and lung cancer risk, with CH mutations occurring more frequently in cases (11.39%) compared to controls (8.62%, p < 0.001). The presence of CH was associated with a 26% (HR 1.260; 95% CI 1.132-1.403) increased risk of lung cancer and showed higher metastasis rates (HR 1.268; 95% CI 1.107-1.452), particularly in individuals with multiple mutations or a variant allele frequency (VAF) ≥ 10%. Additionally, baseline CH mutations were correlated with an 18.4% increase in all-cause mortality and a 21.3% increase in lung cancer-specific mortality. Inflammatory markers partially mediate the relationship between CH and lung cancer incidence. Finally, MR analysis validated the causal role of CHIP on the lung cancer incidence. CH is associated with increased risk of lung cancer and death apart from the known risk factors.