Cross-ancestry Genomic Data Reveal New Susceptibility Loci in Lung Cancer

Genome-wide association studies (GWAS) have identified a large number of genetic variants associated with lung cancer risk; however, many of these studies have focused on individuals of European ancestry (EUR). Multiancestry studies are useful in providing heritability and genetic architecture of disease across diverse populations; therefore, Byun, Han, Li, Xia, Long, and colleagues performed cross-ancestry GWAS studies in EUR, East Asian (EAS), and African (AFR) populations to comprehensively characterize both common and rare genetic risk loci. These studies included over 70,000 individuals with 74% being of EUR ancestry, 18% of EAS ancestry, and 8% of AFR ancestry, and the findings were validated in over 900,000 individuals of similar ancestral proportions. Using stringent criteria to allow for genome-wide discovery across all lung cancer and histologic subtypes, 26 association signals with cross-ancestry variants across all three population models were identified, with nine signals with overall lung cancer, 10 for adenocarcinoma (ADE), six for squamous cell carcinoma (SQC), and one for small cell lung carcinoma (SCC). These included known variants such as BRCA2, CHEK2, and ATM as well as 10 gene regions that included new variants from well-established loci and those associated with smoking behaviors, like CHRNA5 and CYP2A6, which also demonstrated population specificity. Additionally, five new susceptibility variants, including two in overall lung cancer, one in ADE, one in SQC, and one in SCC, were reported, with an intronic variant in IRF4 being among them. Prioritization and characterization of candidate genes for functional annotation indicated that several promote immune response as well as cellular stress response. Additionally, many also revealed a role in altering levels of DNA damage, including IRF4, FUBP1, ACTR2, PPIL6, and AK9. Overall, this study aided in the elucidation of the etiology and mechanisms of lung cancer across multiancestry populations and assists in identifying biomarkers that could be used for early detection and diagnosis as well as treatment of this disease.

Byun J, Han Y, Li Y, Xia J, Long E, Choi J, et al. Cross-ancestry genome-wide meta-analysis of 61,047 cases and 947,237 controls identifies new susceptibility loci contributing to lung cancer. Nat Genet 2022;54:1167–77.

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