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Hum Mol Genet. 2014 Nov 15;23(22):6112-8. doi: 10.1093/hmg/ddu312. Epub 2014 Jun 18.

Most common 'sporadic' cancers have a significant germline genetic component.

Author information

1
Statistical Genetics.
2
Cancer Control Group.
3
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
Molecular Cancer Epidemiology.
5
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, and Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
6
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, and.
7
Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
8
Oncogenomics and.
9
Cancer Genetics, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
10
Statistical Genetics, stuart.macgregor@qimrberghofer.edu.au.

Abstract

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, h(2)g) to twelve cancer types. The following cancers showed a significant (P < 0.05) array heritability: melanoma USA set h(2)g = 0.19 (95% CI = 0.01-0.37) and Australian set h(2)g = 0.30 (0.10-0.50); pancreatic h(2)g = 0.18 (0.06-0.30); prostate h(2)g = 0.81 (0.32-1); kidney h(2)g = 0.18 (0.04-0.32); ovarian h(2)g = 0.30 (0.18-0.42); esophageal adenocarcinoma h(2)g = 0.24 (0.14-0.34); esophageal squamous cell carcinoma h(2)g = 0.19 (0.07-0.31); endometrial UK set h(2)g = 0.23 (0.01-0.45) and Australian set h(2)g = 0.39 (0.02-0.76). Three cancers showed a positive but non-significant effect: breast h(2) g = 0.13 (0-0.56); gastric h(2)g = 0.11 (0-0.27); lung h(2)g = 0.10 (0-0.24). One cancer showed a small effect: bladder h(2)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.

PMID:
24943595
PMCID:
PMC4271103
DOI:
10.1093/hmg/ddu312
[Indexed for MEDLINE]
Free PMC Article

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