Context: Common cancers are frequently demarcated into ‘hereditary’ (or ‘familial’) or ‘sporadic’ (or ‘non-hereditary’) types. Such distinctions initially arose from work identifying rare highly penetrant germline mutations causing ‘hereditary’ cancer. Rare mutations are important in particular families but most cases in the general population are ‘sporadic’. Previous twin studies have suggested that many ‘sporadic’ cancers show little or no heritability.
Objective: To estimate the proportion of variance in cancer liability that can be explained by genetic variants that are common in the general population.
Methods: We apply a method (GCTA) for estimating the variance explained by common variants to several cancer (>1000 cases per cancer) genome-wide association studies (GWASs).
Results: For most cancer types we show that there is a ‘polygenetic’ component underlying liability to cancer. This component is only estimated from common polymorphisms and hence provides a lower bound on the heritability. The following cancers showed a significant polygenic effect: melanoma variance explained (VE)=0.19 (standard error 0.09); pancreatic VE=0.18(0.06); prostate VE=0.81(0.24); renal cell carcinoma VE 0.18(0.08). Two further cancers showed a positive but non-significant effect: breast VE=0.13(0.22); lung VE=0.10(0.07). One cancer showed no effect: bladder VE=0.01(0.04). Amongst these cancers, previous twin studies were only able to clearly show heritability for prostate cancer. Here, for melanoma, renal cell carcinoma and pancreatic cancer we can now make much stronger statements which emphasize the important role of genetic variants in determining risk of these cancers. We show the majority of the ‘polygenic’ component estimated for these cancers is not attributable to the genome-wide significant variants identified by recent GWASs. We demonstrate the robustness of the approach by comparing controls from different studies.
Conclusions: We have demonstrated that several ‘sporadic’ cancers ARE inherited and quantify the genetic component. Conducting larger GWASs in cancer will continue to find ever larger numbers of loci which will explain more of the polygenic component.