Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
Creators: name: Renal Cancer GWAS Consortium
name: Pancreatic Cancer Case-Control Consortium
name: Simard, J.
name: Chen, H.
name: Gaborieau, V.
name: Tyrer, J.
name: Wang, L.
name: Law, M.H.
name: Amos, C.I.
name: Schmit, S.L.
name: Wolpin, B.M.
name: Endometrial Cancer Association Consortium
name: Pancreatic Cancer Cohort Consortium
name: O'Mara, T.A.
name: Ness, A.R.
name: Eeles, R.A.
name: Pasaniuc, B.
name: Feng, H.
name: Lindström, S.
name: Gockel, I.
name: Schumacher, J.
name: Bishop, T.
name: Purdue, M.P.
name: Chanock, S.J.
name: Petersen, G.
name: MacGregor, S.
name: Jones, M.R.
name: McKay, J.D.
name: Majumdar, A.
name: Gharahkhani, P.
name: Esophageal Cancer GWAS Consortium
name: Amundadottir, L.T.
name: Colon Cancer Family Registry Study
name: CRUK
name: Turman, C.
name: Genetics and Epidemiology of Colorectal Cancer Consortium
name: Brown, K.M.
name: Easton, D.
name: Michailidou, K.
name: Cheng, I.C.
name: Melin, B.
name: Glioma International Case Control Consortium
name: Kraft, P.
name: Winham, S.J.
name: PEGASUS
name: Jankowski, J.
name: International Lung Cancer Consortium
name: Kote-Jarai, Z.
name: Li, D.
name: Melanoma GWAS Consortium
name: Brennan, P.
name: Lesseur, C.
name: Colorectal Transdisciplinary Study
name: Christiani, D.C.
name: Landi, M.T.
name: Dennis, J.
name: CAPS
name: Beesley, J.
name: Ovarian Cancer Association Consortium
name: Brossard, M.
name: BPC3
name: Kar, S.
name: Iles, M.M.
name: Bondy, M.L.
name: Spurdle, A.B.
name: PRACTICAL Consortium
name: Jenkins, R.B.
name: Hung, R.J.
name: Pharoah, P.
name: Houlston, R.S.
name: Huyghe, J.R.
name: Diergaarde, B.
name: Schumacher, F.R.
name: Breast Cancer Association Consortium
name: Olshan, A.F.
name: Haiman, C.A.
name: Head-Neck Cancer GWAS Consortium
name: Klein, A.P.
Publisher: name: Cell Press
Year: 2021

description: 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.