Hum Mol Genet. 2014 Jun 18. pii: ddu312. [Epub ahead of print]
Most common ‘sporadic’ cancers have a significant germline genetic component.
Lu Y, Ek WE, Whiteman D, Vaughan TL, Spurdle AB, Easton DF, Pharoah PD, Thompson DJ, Dunning AM, Hayward NK, Chenevix-Trench G; Q-MEGA and AMFS Investigators; ANECS-SEARCH‡; UKOPS-SEARCH‡; BEACON Consortium‡, Macgregor S.
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.