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

Sep 23, 2026

Clonal hematopoiesis of indeterminate potential (CHIP) is established as a risk factor for hematologic malignancies, yet its impact on solid cancers is incompletely defined. A systematic, gene-specific analysis of CHIP across 19 common solid cancer types used UK Biobank and All of Us cohorts with Cox proportional hazards and nested case-control models. CHIP–solid tumor associations were highly cancer-type specific, with lung cancer showing the strongest effect driven mainly by ASXL1-mutant clones and enriched in smokers, supporting gene-specific CHIP metrics for risk stratification.

LanguageEnglish

CategoryResearch & Report

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Pages23

Reading Time58 min

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bioRxiv preprint doi: [https://doi.org/10.64898/2026.05.21.726910](https://doi.org/10.64898/2026.05.21.726910); this version posted May 26, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Gene-Specific Analysis of Clonal Hematopoiesis Identifies ASXL1 as a Risk Factor for Lung Cancer Zijian Zhang 1,2,3,\# , Jing Dong 1,2,3,\# , Yun Huang4 , Yanhong Liu 1 , Christopher I Amos5,6 , Chao Cheng 1,2,3 1Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas 2 Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas 3 Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas 4 Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA 5 University of New Mexico Comprehensive Cancer Center, Albuquerque, New Mexico 6 University of New Mexico Health Sciences Center, Albuquerque, New Mexico \#Contributed equally to this work. Correspondence: Chao Cheng: Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. Telephone: +17137983332, Email: [chao.cheng@bcm.edu](chao.cheng@bcm.edu) Disclosure All the authors declare no conflict of interest. Funding The work was supported by the Cancer Prevention Research Institute of Texas (CPRIT)[RR18006, RP240380] to C.C. , the National Cancer Institute of the National Institutes of Health [R01CA269764] to C.C. , and [R01CA285882] to [Y.L. C.C. is](Y.L. C.C. is) a CPRIT Scholar in Cancer Research. Running title: ASXL1-Driven CHIP and Lung Cancer Risk Word count: 3954 Number of figures and tables: 6 Number of references:44 bioRxiv preprint doi: [https://doi.org/10.64898/2026.05.21.726910](https://doi.org/10.64898/2026.05.21.726910); this version posted May 26, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Abstract 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 cancertype 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-spec

FAQs

What question does the study address about CHIP and cancer risk?

The study evaluates how gene-specific CHIP relates to risk across 19 solid cancer types, noting that CHIP’s role in solid cancers is not fully resolved.

Which solid cancer showed the strongest CHIP association?

Lung cancer exhibited the strongest association, driven largely by ASXL1-mutant clones.

How is the ASXL1 CHIP–lung cancer relationship influenced by smoking?

ASXL1 CHIP was substantially enriched among smokers, and the association with lung cancer risk was restricted to ever-smokers, indicating an interaction between CHIP and environmental exposure.

Sep 23, 2026

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