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Germline copy number variants and endometrial cancer risk

Stylianou, Cassie E. ; Wiggins, George A.R. ; Lau, Vanessa L. ; Dennis, Joe ; Shelling, Andrew N. ; Wilson, Michelle ; Sykes, Peter ; Amant, Frederic ; Annibali, Daniela and De Wispelaere, Wout , et al. (2024) In Human Genetics 143(12). p.1481-1498
Abstract

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10–63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01)... (More)

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10–63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Human Genetics
volume
143
issue
12
pages
18 pages
publisher
Springer
external identifiers
  • pmid:39495297
  • scopus:85208458366
ISSN
0340-6717
DOI
10.1007/s00439-024-02707-9
language
English
LU publication?
yes
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Publisher Copyright: © The Author(s) 2024.
id
5724a147-44be-43b0-9a43-852667b34545
date added to LUP
2025-01-09 09:45:10
date last changed
2025-01-23 11:33:27
@article{5724a147-44be-43b0-9a43-852667b34545,
  abstract     = {{<p>Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10<sup>–63</sup>). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p &lt; 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.</p>}},
  author       = {{Stylianou, Cassie E. and Wiggins, George A.R. and Lau, Vanessa L. and Dennis, Joe and Shelling, Andrew N. and Wilson, Michelle and Sykes, Peter and Amant, Frederic and Annibali, Daniela and De Wispelaere, Wout and Easton, Douglas F. and Fasching, Peter A. and Glubb, Dylan M. and Goode, Ellen L. and Lambrechts, Diether and Pharoah, Paul D.P. and Scott, Rodney J. and Tham, Emma and Tomlinson, Ian and Bolla, Manjeet K. and Couch, Fergus J. and Czene, Kamila and Dörk, Thilo and Dunning, Alison M. and Fletcher, Olivia and García-Closas, Montserrat and Hoppe, Reiner and Sachchithananthan, Mythily and Dinny Graham, J. and Simpson, Peter and Pathmanathan, Nirmala and Davis, Alison and Carpenter, Jane and Yip, Desmond and Baxter, Robert and Scott, Rodney and Marsh, Deborah and Clarke, Christine and Jernström, Helena and Kaaks, Rudolf and Michailidou, Kyriaki and Obi, Nadia and Southey, Melissa C. and Stone, Jennifer and Wang, Qin and Spurdle, Amanda B. and O’Mara, Tracy A. and Pearson, John and Walker, Logan C.}},
  issn         = {{0340-6717}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{1481--1498}},
  publisher    = {{Springer}},
  series       = {{Human Genetics}},
  title        = {{Germline copy number variants and endometrial cancer risk}},
  url          = {{http://dx.doi.org/10.1007/s00439-024-02707-9}},
  doi          = {{10.1007/s00439-024-02707-9}},
  volume       = {{143}},
  year         = {{2024}},
}