Gene-Specific Analysis of Clonal Hematopoiesis Identifies ASXL1 as a Risk Factor for Lung Cancer
Zijian Zhang1,2,3, Jing Dong1,2,3, Yun Huang4
1Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas.
Biorxiv : the Preprint Server for Biology
|June 5, 2026
Summary
Clonal hematopoiesis of indeterminate potential (CHIP) is linked to solid tumors, especially lung cancer. ASXL1-mutant CHIP, particularly in smokers, significantly increases lung cancer risk, suggesting new detection strategies.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- Clonal hematopoiesis of indeterminate potential (CHIP) is a known risk factor for blood cancers.
- Its role in solid tumor development is not fully understood.
Purpose of the Study:
- To investigate the gene-specific association between CHIP and 19 common solid cancer types.
- To identify specific CHIP mutations and risk factors contributing to solid tumor development.
Main Methods:
- Systematic, gene-specific analysis of CHIP in UK Biobank and All of Us cohorts.
- Utilized Cox proportional hazards and nested case-control logistic models.
- Validated findings in MSK-IMPACT and TCGA cancer cohorts.
Main Results:
- CHIP association with solid tumors is cancer-type specific, strongest for lung cancer.
- ASXL1-mutant CHIP, especially high-VAF, significantly increases lung cancer risk (HR=3.2).
- ASXL1 CHIP is enriched in smokers and strongly linked to lung cancer in this group; germline ASXL1 variants also increase lung cancer susceptibility.
Conclusions:
- Smoking-associated ASXL1-mutant clones contribute to lung cancer development.
- Gene-specific CHIP metrics may improve cancer risk stratification and early detection.
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