Most common 'sporadic' cancers have a substantial germline genetic component. S. Macgregor1, W. E. Ek1, Y. Lu1, D. Whiteman1, T. L. Vaughan2, A. B. Spurdle1, D. F. Easton3, P. D. Pharoah3, D. J. Thompson4, A. M. Dunning5, A. K. Hayward1, G. Chenevix-Trench1, Q-MEGA and AMFS Investigators, ANECS-SEARCH, UKOPS-SEARCH, BEACON consortium 1) Queensland Inst Med Res, Brisbane, Australia; 2) Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 3) Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK; 4) Department of Public Health and Primary Care, University of Cambridge, UK; 5) Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.

   Common cancers are frequently demarcated into hereditary or sporadic (non-hereditary) types. 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. Our objective is to quantify the role of common germline genetic variants in cancer susceptibility. We apply a method for estimating the importance of common genetic variants (single nucleotide polymorphism, SNP, heritability, h2g) to several cancer genome-wide association studies (GWASs). Population samples of primarily sporadic cases (>1000 per cancer) and controls were obtained for the following cancers; bladder, breast, endometrial, esophageal, gastric, kidney, lung, melanoma, ovary, pancreatic and prostate.
The following cancers showed a significant (P<0.05) SNP heritability: melanoma USA set h2g =0.19 (standard error 0.09) and Australian set h2g =0.30 (standard error 0.10); pancreatic h2g =0.18 (0.06); prostate h2g =0.81 (0.25); kidney h2g =0.17 (0.07); ovarian h2g =0.30 (0.06); esophageal adenocarcinoma h2g =0.25 (0.05); esophageal squamous cell carcinoma h2g=0.19 (0.05); gastric h2g =0.11 (0.07); endometrial UK set h2g =0.23 (0.11) and Australian set h2g =0.39 (0.19). Two further cancers showed a positive but non-significant effect: breast h2g =0.13 (0.22); lung h2g =0.09 (0.06). One cancer showed a small effect: bladder h2g =0.01 (0.04). Amongst these cancers, previous twin studies were only able to clearly 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. As SNP heritability is only estimated from common SNPs, it provides a lower bound on the overall genetic component (heritability). In analyses with previously identified loci removed, in most instances a significant polygenic component remained. We have demonstrated that several sporadic cancers have a substantial inherited component. Larger GWASs in these cancers will continue to find more loci which explain part of the remaining polygenic component. For most cancers examined here, the descriptor sporadic or non-hereditary should be replaced by polygenic.

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