Clonal blood mutations in ASXL1 associate with higher lung cancer risk
Researchers analyzing two large human cohorts found that ASXL1-mutant clonal hematopoiesis linked to more than triple the risk of lung cancer in smokers.
In human participants from the UK Biobank and the All of Us research programs, investigators analyzed clonal hematopoiesis of indeterminate potential across 19 common solid cancer types. They used Cox proportional hazards models and nested case-control logistic models to evaluate gene-specific risks.
The relationship between clonal hematopoiesis and solid tumors proved highly cancer-type specific, with lung cancer showing the strongest association. This connection was largely driven by ASXL1-mutant clones. Individuals with high variant allele fraction ASXL1 mutations had a hazard ratio of 3.2 for lung cancer. This link remained robust after adjusting for age, sex, body mass index, smoking status, and genetic ancestry. ASXL1 mutations were substantially enriched among smokers, and the increased risk was restricted to ever-smokers. Independent cohorts, MSK-IMPACT and TCGA, validated the ASXL1 enrichment.
Why it matters
Clonal hematopoiesis demonstrates how somatic mutations in blood cells interact with environmental exposures to influence solid tissue pathology. Identifying gene-specific mutant clones provides a clearer picture of how somatic mosaicism contributes to cancer vulnerability.
Caveats
The findings rely on observational cohort data and do not establish a direct causal mechanism between ASXL1 mutations and tumor growth. Furthermore, the elevated lung cancer risk was restricted entirely to ever-smokers.
- Smoking
- Genomic instability
- ASXL1
- Cancer
- Lung cancer
- ASXL1 mutation
- Clonal hematopoiesis of indeterminate potential
- Homo sapiens
The paper
Gene-Specific Analysis of Clonal Hematopoiesis Identifies the Association between ASXL1 and Lung Cancer Risk
Zhang Z, Dong J, Huang Y et al.
Journal of Thoracic Oncology · 28 Sep 2026