Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.
Creators: name: Chen, Hongjie
name: Majumdar, Arunabha
name: Wang, Lu
name: Kar, Siddhartha
name: Brown, Kevin M
name: Feng, Helian
name: Turman, Constance
name: Dennis, Joe
name: Easton, Douglas
name: Michailidou, Kyriaki
name: Simard, Jacques
name: Bishop, Timothy
name: Cheng, Iona C
name: Huyghe, Jeroen R
name: Schmit, Stephanie L
name: O'Mara, Tracy A
name: Spurdle, Amanda B
name: Gharahkhani, Puya
name: Schumacher, Johannes
name: Jankowski, Janusz
name: Gocke, Ines
name: Bondy, Melissa L
name: Houlston, Richard S
name: Jenkins, Robert B
name: Melin, Beatrice
name: Lesseur, Corina
name: Ness, Andy R
name: Diergaarde, Brenda
name: Olshan, Andrew F
name: Amos, Christopher I
name: Christiani, David C
name: Landi, Maria T
name: McKay, James D
name: Brossard, Myriam
name: Iles, Mark M
name: Law, Matthew H
name: MacGregor, Stuart
name: Beesley, Jonathan
name: Jones, Michelle R
name: Tyrer, Jonathan
name: Winham, Stacey J
name: Klein, Alison P
name: Petersen, Gloria
name: Li, Donghui
name: Wolpin, Brian M
name: Eeles, Rosalind A
name: Haiman, Christopher A
name: Kote-Jarai, Zsofia
name: Schumacher, Fredrick R
name: Brennan, Paul
name: Chanock, Stephen J
name: Gaborieau, Valerie
name: Purdue, Mark P
name: Pharoah, Paul
name: Hung, Rayjean J
name: Amundadottir, Laufey T
name: Kraft, Peter
name: Pasaniuc, Bogdan
name: Lindström, Sara
Publisher: name: Apollo - University of Cambridge Repository
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 <i>TERT</i> and <i>CLPTM1L</i> 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.