Genome-wide analyses characterize shared heritability among cancers and identify novel cancer susceptibility regions

全基因组关联研究 癌症 生物 遗传关联 遗传力 前列腺癌 乳腺癌 结直肠癌 遗传学 胰腺癌 单核苷酸多态性 肿瘤科 医学 基因型 基因
作者
Sara Lindström,Lu Wang,Helian Feng,Årindam Majumdar,Sijia Huo,James W. MacDonald,Tabitha A. Harrison,Constance Turman,Hongjie Chen,Nicholas Mancuso,Theo K. Bammler,Steve Gallinger,Stephen B. Gruber,Marc J. Gunter,Loı̈c Le Marchand,Vı́ctor 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 S. Barnholtz‐Sloan,Melissa L. Bondy,Richard S. Houlston,Robert B. Jenkins,Beatrice Melin,Margaret Wrensch,Paul Brennan,Christiani Dc,Mattias Johansson,James McKay,Melinda C. Aldrich,Christopher I. Amos,Maria Teresa Landi,Adonina Tardón,D. Timothy Bishop,Florence Demenais,Alisa M. Goldstein,Mark M. Iles,Peter A. Kanetsky,Matthew Law,Laufey T. Ámundadóttir,Rachael Z. Stolzenberg‐Solomon,Brian M. Wolpin,Alison P. Klein,Gloria M. Petersen,Harvey A. Risch,Stephen J. Chanock,Mark P. Purdue,Ghislaine Scélo,Paul D.P. Pharoah,Siddhartha Kar,Rayjean J. Hung,Bogdan Paşaniuc,Peter Kraft
出处
期刊:Journal of the National Cancer Institute [Oxford University Press]
卷期号:115 (6): 712-732 被引量:2
标识
DOI:10.1093/jnci/djad043
摘要

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.
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