Recent studies have found that cancer-testis (CT) genes, which are expressed predominantly in germ and cancer cells, may be candidate cancer drivers. Because of their crucial roles, genetic variants in these genes may contribute to the development of cancer. Here, we systematically evaluated associations of common variants in CT genes and their promoters for the risk of lung cancer in our initial GWAS (2331 cases and 3077 controls), followed by in silico replication using additional 10,512 lung cancer cases and 9562 controls. We found a significant association between rs3747093 located in the CCDC116 promoter and lung cancer risk (OR = 0.91, P meta = 7.81 × 10-6). Although CCDC116 was expressed at lower levels in somatic tissues compared to the testis, the protective allele A of rs3747093 was associated with decreased CCDC116 expression in many normal tissues, including the lung (P = 8.1 × 10-13). We subsequently genotyped this variant in another four commonly diagnosed cancers (gastric, esophageal, colorectal, and breast cancers), as we found expression quantitative trait locus (eQTL) signals for rs3747093 and CCDC116 in their corresponding normal tissues. Interestingly, we observed consistent associations between rs3747093 and multiple cancers (gastric cancer: OR = 0.85, P = 2.21 × 10-4; esophageal cancer: OR = 0.91, P = 2.57 × 10-2; colorectal cancer: OR = 0.80, P = 1.85 × 10-6; and breast cancer: OR = 0.87, P = 1.55 × 10-3). Taken together, the A allele of rs3747093 showed significant protective effects on cancer risk (OR = 0.88, P pool = 6.52 × 10-13) in an Asian population. Moreover, our findings suggest that low abundance expression of CT genes in normal tissues may also contribute to tumorigenesis, providing a new mechanism of CT genes in the development of cancer.