Identification of Genetic Variants Associated with Sex-Specific Lung-Cancer Risk

SIMPLE SUMMARY: 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, such as smoking rates, may account for much of the risk, another possibility is that X chromosome susceptibility genes may have an effect. Therefore, in this study, we tested specifically for the influence of X chromosome single-nucleotide polymorphisms (SNPs) in male lung cancer cases, and found 24 that were significantly associated with male, but not female, lung cancer cases. Examining these in detail, we observed these SNPs resided in blocks near the annotated genes DMD, PTCHD1-AS, and AL008633.1. We also observed that DMD was differentially expressed in lung cancer subtypes curated in the Cancer Genome Atlas database. Examining this gene further, we found that expression and mutation of DMD may have effects on immune function. This work defines potential targets for sex-specific lung cancer prevention. ABSTRACT: 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.