Germline copy number variants and endometrial cancer risk
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 < 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.
Authors
- Nirmala Pathmanathan (ORCID: https://orcid.org/0000-0001-9225-139X)
- Logan C. Walker (ORCID: https://orcid.org/0000-0003-0018-3719)
- Peter Sykes
- Desmond Yip (ORCID: https://orcid.org/0000-0002-2806-2401)
- Emma Tham (ORCID: https://orcid.org/0000-0001-6079-164X)
- Rodney J. Scott
- Helena Jernström (ORCID: https://orcid.org/0000-0002-2301-5147)
- Thilo Dörk (ORCID: https://orcid.org/0000-0002-9458-0282)
- Frédéric Amant (ORCID: https://orcid.org/0000-0002-5452-4905)
- Dylan M. Glubb
- Joe Dennis (ORCID: https://orcid.org/0000-0003-4591-1214)
- Andrew N. Shelling (ORCID: https://orcid.org/0000-0002-5300-1934)
- Rudolf Kaaks (ORCID: https://orcid.org/0000-0003-3751-3929)
- Peter T. Simpson (ORCID: https://orcid.org/0000-0002-4816-8289)
- Michelle Wilson (ORCID: https://orcid.org/0000-0003-0287-7829)
- Alison M. Dunning (ORCID: https://orcid.org/0000-0001-6651-7166)
- Kamila Czene (ORCID: https://orcid.org/0000-0002-3233-5695)
- Ian Tomlinson (ORCID: https://orcid.org/0000-0003-3037-1470)
- Alison J. Davis (ORCID: https://orcid.org/0000-0003-4425-7871)
- Mythily Sachchithananthan (ORCID: https://orcid.org/0000-0002-8547-1308)
- Wout De Wispelaere (ORCID: https://orcid.org/0000-0002-7513-9002)
- Kyriaki Michailidou (ORCID: https://orcid.org/0000-0001-7065-1237)
- Daniela Annibali (ORCID: https://orcid.org/0000-0001-8413-7669)
- Cassie E. Stylianou
- Esther M. John (ORCID: https://orcid.org/0000-0003-3259-8003)
- Deborah J. Marsh (ORCID: https://orcid.org/0000-0001-5899-4931)
- Christine L. Clarke (ORCID: https://orcid.org/0000-0001-7568-111X)
- Jennifer Stone (ORCID: https://orcid.org/0000-0001-5077-0124)
- Nadia Obi (ORCID: https://orcid.org/0000-0002-0903-9142)
- Olivia Fletcher (ORCID: https://orcid.org/0000-0003-4436-5143)
- Tracy A. O’Mara (ORCID: https://orcid.org/0000-0002-5436-3232)
- Montserrat García‐Closas (ORCID: https://orcid.org/0000-0003-1033-2650)
- George A. R. Wiggins (ORCID: https://orcid.org/0000-0003-2471-2267)
- J Dinny Graham
- Melissa C. Southey (ORCID: https://orcid.org/0000-0002-6313-9005)
- Qin Wang (ORCID: https://orcid.org/0000-0002-9139-0627)
- Reiner Hoppe (ORCID: https://orcid.org/0000-0003-2213-9612)
- Diether Lambrechts
- Jane Carpenter
- Peter A. Fasching
- V. Lau
- Amanda B. Spurdle (ORCID: https://orcid.org/0000-0003-1337-7897)
- Paul D. P. Pharoah
- Ellen L. Goode
- Robert Baxter
- Fergus J. Couch
- Douglas F. Easton
- Manjeet K. Bolla (ORCID: https://orcid.org/0000-0002-4351-9326)
- Rodney Scott
Institutions
- Cedars-Sinai Medical Center (US)
- Karolinska University Hospital (SE)
- Institute of Cancer Research (GB)
- University of Auckland (NZ)
- Universität Hamburg (DE)
- The University of Melbourne (AU)
- The University of Western Australia (AU)
- German Cancer Research Center (DE)
- Lund University (SE)
- Cancer Council Victoria (AU)
- QIMR Berghofer Medical Research Institute (AU)
- Heidelberg University (DE)
- University of Cambridge (GB)
- Breast Cancer Now (GB)
- John Hunter Hospital (AU)
- Auckland City Hospital (NZ)
- Karolinska Institutet (SE)
- Medizinische Hochschule Hannover (DE)
- University of Oxford (GB)
- Hunter Medical Research Institute (AU)
- Universitätsklinikum Erlangen (DE)
- Cancer Research UK Cambridge Center (GB)
- VIB-KU Leuven Center for Cancer Biology (BE)
- University Medical Center Hamburg-Eppendorf (DE)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- Monash Health (AU)
- Mayo Clinic in Arizona (US)
- Mayo Clinic in Florida (US)
- Comprehensive Cancer Center Erlangen (DE)
- Cyprus Institute of Neurology and Genetics (CY)
- Monash University (AU)
- University of Newcastle Australia (AU)
- University of Otago (NZ)
- University of Tübingen (DE)
- KU Leuven (BE)
Publication Details
- Journal
- Human Genetics
- Published
- 2024-11-04
- DOI
- https://doi.org/10.1007/s00439-024-02707-9
- Citations
- 2
- Primary Topic
- Genomic variations and chromosomal abnormalities
- Type
- article
- Field-Weighted Citation Impact
- 1.10
Funders
- Deutsches Krebsforschungszentrum
- Genome Canada
- Fondation du cancer du sein du Québec
- Government of Canada
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- European Commission
- National Breast Cancer Foundation
- Cancer Institute NSW
- Deutsche Forschungsgemeinschaft
- Bundesministerium für Bildung und Forschung
- Fonds Wetenschappelijk Onderzoek
- Deutsche Gesetzliche Unfallversicherung
- Deutsche Krebshilfe
- National Institutes of Health
- Canadian Institutes of Health Research
- Medical Research Council
- National Health and Medical Research Council
- Cancer Council Western Australia
- Health Research Council of New Zealand
- NIHR Cambridge Biomedical Research Centre
- National Cancer Institute