Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals

Chen, Hongjie and Majumdar, Arunabha and Wang, Lu and et al, . (2021) Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals. Human Genetics and Genomics Advances, 2 (3). pp. 1-17. ISSN 2666-2477

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Abstract

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. © 2021 The Authors

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IITH Creators:

IITH Creators	ORCiD
Majumdar, Arunabha	https://orcid.org/0000-0002-5609-075X

Item Type:

Article

Additional Information:

B.M.W. has received research grants from Celgene and Eli Lilly and has consulting relationship with BioLineRx, Celgene, and Grail. R.A.E. has received speaker honoraria from the GU-ASCO meeting (January 2016), RMH FR meeting (November 2017, supported by Janssen), University of Chicago invited talk (May 2018), and ESMO (September 2019, supported by Bayer & Ipsen) and served as member of external expert committee at the Prostate Dx Advisory Panel (June 2020). All other authors declare no competing interests.

Uncontrolled Keywords:

5p15.33 region; cancer; CLPTM1L; fine-mapping; pleiotropy; TERT 5p15.33 region; cancer; CLPTM1L; fine-mapping; pleiotropy; TERT

Subjects:

Mathematics

Divisions:

Department of Mathematics

Depositing User:

. LibTrainee 2021

Date Deposited:

03 Sep 2022 05:21

Last Modified:

03 Sep 2022 05:21