Clonal Hematopoiesis and Risk of Incident Lung Cancer

Abstract

Purpose: To prospectively examine the association between clonal hematopoiesis (CH) and subsequent risk of lung cancer.

Methods: Among 200,629 UK Biobank (UKBB) participants with whole-exome sequencing, CH was identified in a nested case-control study of 832 incident lung cancer cases and 3,951 controls (2006-2019) matched on age and year at blood draw, sex, race, and smoking status. A similar nested case-control study (141 cases/652 controls) was conducted among 27,975 participants with whole-exome sequencing in the Mass General Brigham Biobank (MGBB, 2010-2021). In parallel, we compared CH frequency in published data from 5,003 patients with solid tumor (2,279 lung cancer) who had pretreatment blood sequencing performed through Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets.

Results: In UKBB, the presence of CH was associated with increased risk of lung cancer (cases: 12.5% v controls: 8.7%; multivariable-adjusted odds ratio [OR], 1.36; 95% CI, 1.06 to 1.74). The association remained robust after excluding participants with chronic obstructive pulmonary disease. No significant interactions with known risk factors, including polygenic risk score and C-reactive protein, were identified. In MGBB, we observed similar enrichment of CH in lung cancer (cases: 15.6% v controls: 12.7%). The meta-analyzed OR (95% CI) of UKBB and MGBB was 1.35 (1.08 to 1.68) for CH overall and 1.61 (1.19 to 2.18) for variant allele frequencies ≥ 10%. In Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, CH with a variant allele frequency ≥ 10% was enriched in pretreatment lung cancer compared with other tumors after adjusting for age, sex, and smoking (OR for lung v breast cancer: 1.61; 95% CI, 1.03 to 2.53).

Conclusion: Independent of known risk factors, CH is associated with increased risk of lung cancer.

FIG 1.

Frequency of CH mutations among incident lung cancer cases and controls, UKBB. (A) Frequency of overall CH mutations (general additive modeling with spline smoothing) by case-control status and age at blood draw. (B) CH mutations with VAF 2% to < 10%. (C) CH mutations with VAF ≥ 10%. (D) The top 10 most frequent mutated CH genes according to case-control status. CH, clonal hematopoiesis; UKBB, UK Biobank; VAF, variant allele frequency.

FIG 2.

CH and risk of incident lung cancer according to (A) lung cancer risk factors and (B) lung cancer characteristics, UKBB. All models were adjusted for age and year at blood draw, sex (female/male), race (White/others), smoking status (never/past/current smoker), pack-years of smoking (continuous), family history of lung cancer (no/yes), and the first 10 principal components of genetic ancestry. Stratified analyses by PRS were additionally adjusted for genotype array (BiLEVE/Axiom) and standardized lung cancer PRS (continuous). Stratified analyses by CRP were additionally adjusted for CRP (continuous). P for interaction was estimated using the Wald test. P for heterogeneity was estimated using polytomous logistic regression. CH, clonal hematopoiesis; CRP, C-reactive protein; OR, odds ratio; PRS, polygenic risk score; UKBB, UK Biobank.

FIG 3.

Meta-analyzed association between CH and risk of incident lung cancer, UKBB and MGBB. Meta-analyzed ORs were bolded. CH-negative individuals were considered as the referent group in all models. All models were adjusted for age and year at blood draw, sex (female/male), race (White/others), smoking status (never/past/current smoker), pack-years of smoking (continuous), family history of lung cancer (no/yes), and the first 10 principal components of genetic ancestry. P for heterogeneity was estimated using Cochran's Q test. CH, clonal hematopoiesis; MGBB, Mass General Brigham Biobank; OR, odds ratio; UKBB, UK Biobank; VAF, variant allele frequency.

FIG 4.

Comparison of CH frequency overall and according to VAF using pretreatment blood samples from patients with major solid tumors, MSK-IMPACT. (A) Frequency of CH mutations in the five most common cancer subtypes. (B) Differential associations between CH and the cancer type, using breast carcinoma as the referent cancer type. (C) Differential associations between CH and the cancer type for VAF 2% to < 10%, using breast cancer as the referent cancer type. (D) Differential associations between CH and the cancer type for VAF ≥ 10%, using breast carcinoma as the referent cancer type. All models were adjusted for age at diagnosis/blood draw, sex (female/male), and smoking status (never/ever). CH, clonal hematopoiesis; MSK‐IMPACT, Memorial Sloan Kettering‐Integrated Mutation Profiling of Actionable Cancer Targets; OR, odds ratio; VAF, variant allele frequency.