Germline copy number variants and endometrial cancer risk

Stylianou CE, Wiggins GA, Lau VL, Dennis J, Shelling AN, Wilson M, Sykes P, Amant F, Annibali D, De Wispelaere W, Easton DF, Fasching P, Glubb DM, Goode EL, Lambrechts D, Pharoah PD, Scott RJ, Tham E, Tomlinson I, Bolla MK, Couch FJ, Czene K, Dörk T, Dunning AM, Fletcher O, García-Closas M, Hoppe R, Sachchithananthan M, Dinny Graham J, Simpson P, Pathmanathan N, Davis A, Carpenter J, Yip D, Baxter R, Scott R, Marsh D, Clarke C, Jernström H, Kaaks R, Michailidou K, Obi N, Southey MC, Stone J, Wang Q, Spurdle AB, O’Mara TA, Pearson J, Walker LC (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1007/s00439-024-02707-9

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) 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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Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Mayo Clinic United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Cedars-Sinai Medical Center United States (USA) (US) John Hunter Hospital Australia (AU) Karolinska Institute Sweden (SE) University of Oxford United Kingdom (GB) University of Cambridge United Kingdom (GB) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) The Institute of Cancer Research (ICR) United Kingdom (GB) Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie Germany (DE) Lund University / Lunds universitet Sweden (SE) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Monash University Australia (AU) University of Western Australia (UWA) Australia (AU) University of Otago New Zealand (NZ) University of Auckland New Zealand (NZ) Auckland City Hospital New Zealand (NZ) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE)

How to cite

APA:

Stylianou, C.E., Wiggins, G.A., Lau, V.L., Dennis, J., Shelling, A.N., Wilson, M.,... Walker, L.C. (2024). Germline copy number variants and endometrial cancer risk. Human genetics. https://doi.org/10.1007/s00439-024-02707-9

MLA:

Stylianou, Cassie E., et al. "Germline copy number variants and endometrial cancer risk." Human genetics (2024).

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