Citation
Chen, Hongjie; Majumdar, Arunabha; Wang, Lu; Kar, Siddhartha; Brown, Kevin M.; Feng, Helian; Turman, Constance; Dennis, Joe; Easton, Douglas F.; & Michailidou, Kyriaki, et al. (2021). Large-Scale Cross-Cancer Fine-Mapping of the 5p15.33 Region Reveals Multiple Independent Signals. HGG Advances, 2(3), 100041. PMCID: PMC8336922Abstract
Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.URL
http://dx.doi.org/10.1016/j.xhgg.2021.100041Reference Type
Journal ArticleYear Published
2021Journal Title
HGG AdvancesAuthor(s)
Chen, HongjieMajumdar, Arunabha
Wang, Lu
Kar, Siddhartha
Brown, Kevin M.
Feng, Helian
Turman, Constance
Dennis, Joe
Easton, Douglas F.
Michailidou, Kyriaki
Simard, Jacques
Breast Cancer Association Consortium (BCAC),
Bishop, Timothy
Cheng, Iona
Huyghe, Jeroen R.
Schmit, Stephanie L.
Colorectal Transdisciplinary Study (CORECT),
Colon Cancer Family Registry Study (CCFR),
Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO),
O'Mara, Tracy A.
Spurdle, Amanda B.
Endometrial Cancer Association Consortium (ECAC),
Gharahkhani, Puya
Schumacher, Johannes
Jankowski, Janusz
Gocke, Ines
Esophageal Cancer GWAS Consortium,
Bondy, Melissa L.
Houlston, Richard S.
Jenkins, Robert B.
Melin, Beatrice
Glioma International Case Control Consortium (GICC),
Lesseur, Corina
Ness, Andy R.
Diergaarde, Brenda
Olshan, Andrew F.
Head-Neck Cancer GWAS Consortium,
Amos, Christopher I.
Christiani, David C.
Landi, Maria T.
McKay, James D.
International Lung Cancer Consortium (ILCCO),
Brossard, Myriam
Iles, Mark M.
Law, Matthew H.
MacGregor, Stuart
Melanoma GWAS Consortium,
Beesley, Jonathan
Jones, Michelle R.
Tyrer, Jonathan
Winham, Stacey J.
Ovarian Cancer Association Consortium (OCAC),
Klein, Alison P.
Petersen, Gloria
Li, Donghui
Wolpin, Brian M.
Pancreatic Cancer Case-Control Consortium (PANC4),
Pancreatic Cancer Cohort Consortium (PanScan),
Eeles, Rosalind A.
Haiman, Christopher A.
Kote-Jarai, Zsofia
Schumacher, Fredrick R.
PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS,
Brennan, Paul
Chanock, Stephen J.
Gaborieau, Valerie
Purdue, Mark P.
Renal Cancer GWAS Consortium,
Pharoah, Paul
Hung, Rayjean J.
Amundadottir, Laufey T.
Kraft, Peter
Pasaniuc, Bogdan
Lindström, Sara