Gene-Specific Analysis of Clonal Hematopoiesis Identifies ASXL1 as a Risk Factor for Lung Cancer.

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a recognized risk factor for hematologic malignancies, but its contribution to different types of solid cancers remains incompletely defined. Methods: Here, we performed a systematic, gene-specific analysis of CHIP across 19 common solid cancer types using two large population-based cohorts, the UK Biobank and All of Us with Cox proportional hazards models and nested case-control logistic models. Results: We demonstrate that the relationship between CHIP and solid tumors is highly cancer-type specific, with lung cancer exhibiting the strongest association. In lung cancer, this association is largely driven by ASXL1-mutant clones. Specifically, high variant allele fraction (high-VAF) ASXL1 conferring a significantly increased risk (hazard ratio = 3.2), and the associations remained robust after adjustment for age, sex, body mass index (BMI), smoking status, and genetic ancestry. Notably, ASXL1 CHIP was substantially enriched among smokers, and its association with lung cancer risk was restricted to ever-smokers, highlighting a key interaction between CHIP and environmental exposure. The enrichment of ASXL1 CHIP in lung cancer was further validated in two independent cancer-only cohorts, including MSK-IMPACT and TCGA. In addition, rare germline variant association analysis revealed that germline variation in ASXL1 had the strongest association with lung cancer susceptibility among all solid tumors. Conclusions: Collectively, our findings support a model in which smoking-associated expansion of ASXL1-mutant clones contributes to lung cancer development and suggest that gene-specific CHIP metrics may enhance risk stratification and early detection strategies.