Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions Journal Article
| Authors: | Lindström, S.; Wang, L.; Feng, H. L.; Majumdar, A.; Huo, S. J.; Macdonald, J.; Harrison, T.; Turman, C.; Chen, H.; Mancuso, N.; Bammler, T.; Breast Cancer Association Consortium (BCAC); Gallinger, S.; Gruber, S. B.; Gunter, M. J.; Le Marchand, L.; Moreno, V.; Offit, K.; Colorectal Transdisciplinary Study (CORECT); Colon Cancer Family Registry Study (CCFR); Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO); De Vivo, I.; O'Mara, T. A.; Spurdle, A. B.; Tomlinson, I.; Endometrial Cancer Association Consortium (ECAC); Fitzgerald, R.; Gharahkhani, P.; Gockel, I.; Jankowski, J.; Macgregor, S.; Schumacher, J.; Barnholtz-Sloan, J.; Bondy, M. L.; Houlston, R. S.; Jenkins, R. B.; Melin, B.; Wrensch, M.; Brennan, P.; Christiani, D. C.; Johansson, M.; McKay, J.; Aldrich, M. C.; Amos, C. I.; Landi, M. T.; Tardon, A.; International Lung Cancer Consortium (ILCCO); Bishop, D. T.; Demenais, F.; Goldstein, A. M.; Iles, M. M.; Kanetsky, P. A.; Law, M. H.; Ovarian Cancer Association Consortium (OCAC); Amundadottir, L. T.; Stolzenberg-Solomon, R.; Wolpin, B. M.; Pancreatic Cancer Cohort Consortium (Panscan); Klein, A.; Petersen, G.; Risch, H.; Pancreatic Cancer Case-Control Consortium (Panc4); The PRACTICAL Consortium; Chanock, S. J.; Purdue, M. P.; Scelo, G.; Pharoah, P.; Kar, S.; Hung, R. J.; Pasaniuc, B.; Kraft, P. |
| Article Title: | Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions |
| Abstract: | Background: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from 12 cancer genome-wide association studies (GWAS) to quantify pairwise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.Methods: We collected GWAS summary statistics for 12 solid cancers based on 376 759 participants with cancer and 532 864 participants without cancer of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.Results: We observed widespread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and transcriptome-wide association studies, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least 2 cancer types by testing for pleiotropy at known cancer susceptibility loci.Conclusions: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer-specific and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types. |
| Keywords: | breast; prostate; genetic susceptibility; lung; association; loci; ovarian; atlas; multiple |
| Journal Title: | JNCI: Journal of the National Cancer Institute |
| Volume: | 115 |
| Issue: | 6 |
| ISSN: | 0027-8874 |
| Publisher: | Oxford University Press |
| Date Published: | 2023-06-01 |
| Start Page: | 712 |
| End Page: | 732 |
| Language: | English |
| ACCESSION: | WOS:000975864100001 |
| DOI: | 10.1093/jnci/djad043 |
| PROVIDER: | wos |
| PMCID: | PMC10248849 |
| PUBMED: | 36929942 |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PDF -- Source: Wos |
