Most common ‘sporadic’ cancers have a significant germline genetic component

Common cancers have been demarcated into ‘hereditary’ or ‘sporadic’ (‘non-hereditary’) types historically. Such distinctions initially arose from work identifying rare, highly penetrant germline mutations causing ‘hereditary’ cancer. While rare mutations are important in particular families, most cases in the general population are ‘sporadic’. Twin studies have suggested that many ‘sporadic’ cancers show little or no heritability. To quantify the role of germline mutations in cancer susceptibility, we applied a method for estimating the importance of common genetic variants (array heritability, h²_g) to twelve cancer types. The following cancers showed a significant (P < 0.05) array heritability: melanoma USA set h²_g = 0.19 (95% CI = 0.01–0.37) and Australian set h²_g = 0.30 (0.10–0.50); pancreatic h²_g = 0.18 (0.06–0.30); prostate h²_g = 0.81 (0.32–1); kidney h²_g = 0.18 (0.04–0.32); ovarian h²_g = 0.30 (0.18–0.42); esophageal adenocarcinoma h²_g = 0.24 (0.14–0.34); esophageal squamous cell carcinoma h²_g = 0.19 (0.07–0.31); endometrial UK set h²_g = 0.23 (0.01–0.45) and Australian set h²_g = 0.39 (0.02–0.76). Three cancers showed a positive but non-significant effect: breast h²_g = 0.13 (0–0.56); gastric h²_g = 0.11 (0–0.27); lung h²_g = 0.10 (0–0.24). One cancer showed a small effect: bladder h²_g = 0.01 (0–0.11). Among these cancers, previous twin studies were only able to show heritability for prostate and breast cancer, but we can now make much stronger statements for several common cancers which emphasize the important role of genetic variants in cancer susceptibility. We have demonstrated that several ‘sporadic’ cancers have a significant inherited component. Larger genome-wide association studies in these cancers will continue to find more loci, which explain part of the remaining polygenic component.