New Lung Cancer Susceptibility Loci Detected in Cross-Ancestry GWAS

An international team led by investigators at Baylor College of Medicine has tracked down new variants involved in lung cancer risk using a genome-wide association study meta-analysis that included hundreds of thousands of individuals from multiple ancestral backgrounds.

"Understanding the genetic architecture of lung cancer predisposition will help reveal how lung cancer develops and could assist in identifying new susceptibility markers for better risk evaluation directed at early detection and diagnosis, targeted therapy, and improved preventive measures," senior and corresponding author Christopher Amos, director of BCM's Institute for Clinical and Translational Medicine, and his colleagues explained.

For a study published in Nature Genetics on Monday, the researchers brought together genotyping profiles for 61,047 individuals with lung cancer and more than 947,200 unaffected controls that included participants from European, East Asian, and African ancestry groups from a dozen prior genome-wide association studies.

"Most GWAS have focused on genetically homogeneous case-control studies from European ancestry populations," the authors noted, adding that "cross-ancestry analysis can improve association signal detection for low-frequency and rare alleles if they are more frequent in one population and help pinpoint functional variants when there is variability in linkage disequilibrium (LD) between functional variants and marker alleles across populations."

Along with variants implicated in lung cancer risk in past studies, the team highlighted several previously undetected variant associations at known loci as well as five loci not reported in the past. The risk variant collection encompassed lung cancer susceptibility sites specific to certain populations or lung cancer histological subtypes, such as lung adenocarcinoma, lung squamous cell carcinoma, or small cell lung carcinoma.

While lung cancer risk in general coincided with 15 risk loci across the ancestry groups, the researchers linked 14 new and known risk loci to adenocarcinoma. They also detected nine squamous cell carcinoma-related sites and two loci associated with small cell lung carcinoma.

Their analysis also pointed to rare and more common risk variants that appeared to have population-specific effects on lung cancer risk, including a rare IL17RC variant implicated in small cell carcinoma in individuals with European or African ancestry and a low-frequency HCG15 gene variant with ties to small cell lung carcinoma in African ancestry participants.

"Rare-variant associations tended to be specific to populations," the authors reported, "but even common-variant associations influencing smoking behavior … showed population specificity."

From there, the researchers turned to fine-mapping and expression quantitative trait locus analyses, combined with DNA damage assays, to focus in on several lung cancer-related tissues and 48 candidate genes that appeared to explain some of the new and known lung cancer risk associations detected — a collection that included risk genes from potentially targetable pathways related to DNA damage, cellular stress response, or immune activity.

"Overall," the authors reported, "our cross-ancestry meta-analysis of population-specific GWAS across multi-ancestry populations has helped elucidate the etiology and mechanisms of lung cancer."