全基因组分析表征了癌症之间的共同遗传性并识别出新的癌症易感性区域。
Genome-Wide Analyses Characterize Shared Heritability Among Cancers and Identify Novel Cancer Susceptibility Regions.
发表日期：2023 Mar 17
作者：
Sara Lindström, Lu Wang, Helian Feng, Arunabha Majumdar, Sijia Huo, James Macdonald, Tabitha Harrison, Constance Turman, Hongjie Chen, Nicholas Mancuso, Theo Bammler, , Steve Gallinger, Stephen B Gruber, Marc J Gunter, Loic Le Marchand, Victor Moreno, Kenneth Offit, , Immaculata de Vivo, Tracy A O'Mara, Amanda B Spurdle, Ian Tomlinson, , Rebecca Fitzgerald, Puya Gharahkhani, Ines Gockel, Janusz Jankowski, Stuart Macgregor, Johannes Schumacher, Jill Barnholtz-Sloan, Melissa L Bondy, Richard S Houlston, Robert B Jenkins, Beatrice Melin, Margaret Wrensch, Paul Brennan, David Christiani, Mattias Johansson, James Mckay, Melinda C Aldrich, Christopher I Amos, Maria Teresa Landi, Adonina Tardon, , D Timothy Bishop, Florence Demenais, Alisa M Goldstein, Mark M Iles, Peter A Kanetsky, Matthew H Law, , Laufey T Amundadottir, Rachael Stolzenberg-Solomon, Brian M Wolpin, , Alison Klein, Gloria Petersen, Harvey Risch, , , Stephen J Chanock, Mark P Purdue, Ghislaine Scelo, Paul Pharoah, Siddhartha Kar, Rayjean J Hung, Bogdan Pasaniuc, Peter Kraft
来源：
Environmental Technology & Innovation
摘要：
不完全了解不同癌症风险的共同遗传贡献。在这项研究中，我们利用来自12个癌症全基因组关联研究（GWAS）的结果来量化癌症间基因组范围的遗传相关性，并确定新的癌症易感位点。我们收集了基于376,759个欧洲祖先的癌症病例和532,864个对照的12种实体癌症的GWAS汇总统计数据，包括乳腺癌、结肠直肠癌、子宫内膜癌、食管癌、胶质瘤、头颈癌、肺癌、黑色素瘤、卵巢癌、胰腺癌、前列腺癌和肾癌。我们进行了癌症间GWAS和转录组范围的关联研究（TWAS）以发现新的癌症易感位点。最后，我们评估了已知和新识别的癌症易感位点在癌症变体特异性多效性方面的程度。我们观察到癌症间存在广泛但适度的基因组范围的遗传相关性。在癌症间GWAS和TWAS中，我们确定了15个新的癌症易感位点。此外，我们通过测试已知癌症易感位点的多效性，确定了77个不同位点的多个变异体与至少两种癌症类型存在强有力的相关性证据。总的来说，这些结果表明一些遗传风险变异体在不同癌症间是共享的，尽管癌症遗传可塑性大多是癌症和相关组织特异性的。在跨疾病分析中，样本量的增加提高了统计功率，有助于确定新的易感区域。未来的研究将结合多种癌症类型的数据，可能会发现与多种癌症类型的风险相关的其他区域。©作者2023年。 由Oxford University Press出版。保留所有权利。欲获得权限，请发送电子邮件至：journals.permissions@oup.com。
The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from twelve cancer genome-wide association studies (GWAS) to quantify pair-wise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.We collected GWAS summary statistics for twelve solid cancers based on 376,759 cancer cases and 532,864 controls 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 (TWAS) 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.We observed wide-spread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and TWAS, 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 two cancer types by testing for pleiotropy at known cancer susceptibility loci.Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer- 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.© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.