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.

INTEGRAL‐ILCCO cohort data analysis revealed the association of clonal haematopoiesis with an increased risk of lung cancer

“…In addition, our study used a panel of well‐defined CH genes to identify CH mutations, while Tian et al. focussed on a list of cancer driver mutations in 178 genes 5 . Despite these differences, our analysis in the INTEGRAL‐ILCCO cohort confirmed the primary finding by Tian et al.…”

“…than that in the UKBB cohort. In addition, our study used a panel of well-defined CH genes to identify CH mutations, while Tian et al focussed on a list of cancer driver mutations in 178 genes 5. Despite these differences, our analysis in the INTEGRAL-ILCCO cohort confirmed the primary finding by Tian et al: the presence of CH mutations is associated with an increased risk of lung cancer, which is mainly driven by high-VAF mutations.…”

“…2 Interestingly, a link between CH and other cancers have also been observed. 3 Recently, Tian et al analysed the whole exome sequencing (WES) data from the UK Biobank (UKBB) 4 and the Mass General Brigham Biobank (MGBB) cohorts 5 ; and reported a significant association between CH mutations and lung cancer risk. 5 The association was primarily driven by the expansion of clones harbouring CH mutations with high variant allele frequency (VAF).…”

“…3 Recently, Tian et al analysed the whole exome sequencing (WES) data from the UK Biobank (UKBB) 4 and the Mass General Brigham Biobank (MGBB) cohorts 5 ; and reported a significant association between CH mutations and lung cancer risk. 5 The association was primarily driven by the expansion of clones harbouring CH mutations with high variant allele frequency (VAF). In the UKBB data, after adjusting for age, sex, race and smoking status, subjects with high-VAF CH mutations (VAF ≥ 10%) had an odds ratio (OR) of 1.77, compared to an OR of 1.28 for subjects with low VAF mutations (2%-10%).…”

Clonal hematopoiesis of indeterminate potential and clonal cytopenias of undetermined significance: 2023 update on clinical associations and management recommendations

“…Presence of CH mutations and large chromosomal deletions have been associated with type 2 diabetes mellitus 10 . Similarly, CH (primarily, DNMT3A and TET2 ) occurrence has been associated with occurrence of severe chronic obstructive pulmonary disease, 12 lung cancer, 70 chronic kidney disease, 71 and gout 13 . CH has been associated with increased of stroke; TET2 CH is associated with both overall and ischemic stroke, while DNMT3A is associated with increased risk of hemorrhagic stroke 72,73 .…”