Identification of genetic variants associated with sex-specific lung-cancer risk

Background: The incidence of lung cancer differs between men and women, suggesting the potential role of sex-specific influences in susceptibility to this cancer. While behavioural differences may account for some of the risk, another possibility is that X chromosome susceptibility genes may have an effect. Little is known about genetic variants on the X chromosome that contribute to sex-specific lung-cancer risk, so we investigated this in a previously characterized cohort. Methods: We conducted a genetic association reanalysis of 518 lung cancer patients and 844 controls to test for lung cancer susceptibility variants on the X chromosome. Annotated gene expression, co-expression analysis, pathway, and immune infiltration analyses were also performed. Results: 24 SNPs were identified as significantly associated with male, but not female, lung cancer cases. These resided in blocks near the annotated genes DMD, PTCHD1-AS, and AL008633.1. Of these, DMD was differentially expressed in lung cancer cases curated in The Cancer Genome Atlas. A functional enrichment and a KEGG pathway analysis of co-expressed genes revealed that differences in immune function could play a role in sex-specific susceptibility. Conclusions: Our analyses identified potential genetic variants associated with sex-specific lung cancer risk. Integrating GWAS and RNA-sequencing data revealed potential targets for lung cancer prevention.