Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study

Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Spiewankiewicz B, Myers EJ, Chenevix-Trench G, Fasching PA, Beckmann M, Ekici AB, Hein A, Vergote I, Van Nieuwenhuysen E, Lambrechts D, Wicklund KG, Eilber U, Wang-Gohrke S, Chang-Claude J, Rudolph A, Sucheston-Campbell L, Odunsi K, Moysich KB, Shvetsov YB, Thompson PJ, Goodman MT, Wilkens LR, Doerk T, Hillemanns P, Duerst M, Runnebaum IB, Bogdanova N, Pelttari LM, Nevanlinna H, Leminen A, Edwards RP, Kelley JL, Harter P, Schwaab I, Heitz F, Du Bois A, Orsulic S, Lester J, Walsh C, Karlan BY, Hogdall E, Kjaer SK, Jensen A, Vierkant RA, Cunningham JM, Goode EL, Fridley BL, Southey MC, Giles GG, Bruinsma F, Wu X, Hildebrandt MAT, Lu K, Liang D, Bisogna M, Levine DA, Weber RP, Schildkraut JM, Iversen ES, Berchuck A, Terry KL, Cramer DW, Tworoger SS, Poole EM, Olson SH, Orlow I, Bandera EV, Bjorge L, Tangen IL, Salvesen HB, Krakstad C, Massuger LFAG, Kiemeney LA, Aben KKH, Van Altena AM, Bean Y, Pejovic T, Kellar M, Le ND, Cook LS, Kelemen LE, Brooks-Wilson A, Lubinski J, Gronwald J, Cybulski C, Jakubowska A, Wentzensen N, Brinton LA, Lissowska J, Yang H, Nedergaard L, Lundvall L, Hogdall C, Song H, Campbell IG, Eccles D, Glasspool R, Siddiqui N, Carty K, Paul J, Mcneish LA, Sieh W, Mcguire V, Rothstein JH, Whittemore AS, Mclaughlin JR, Risch HA, Phelan CM, Anton-Culver H, Ziogas A, Menon U, Ramus SJ, Gentry-Maharaj A, Harrington P, Pike MC, Modugno F, Rossing MA, Ness RB, Pharoah PDP, Stram DO, Wu AH, Pearce CL (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Book Volume: 136

Pages Range: 542-8

Journal Issue: 3

DOI: 10.1016/j.ygyno.2014.12.017

Abstract

Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

Authors with CRIS profile

Involved external institutions

University of California Los Angeles (UCLA) United States (USA) (US) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) University of Copenhagen Denmark (DK) National Cancer Institute (NCI) United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) British Columbia Cancer Agency Canada (CA) Alberta Health Services (AHS) Canada (CA) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Oregon Health and Science University (OSHU) United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Rutgers Cancer Institute of New Jersey United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Harvard University United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Duke University United States (USA) (US) Texas Southern University (TSU) United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) Cancer Council Victoria Australia (AU) The University of Melbourne Australia (AU) University of Kansas (KU) United States (USA) (US) Mayo Clinic United States (USA) (US) Danish Cancer Society Denmark (DK) Cedars-Sinai Medical Center United States (USA) (US) Kliniken Essen-Mitte Germany (DE) Institut für Humangenetik Wiesbaden Germany (DE) University of Pittsburgh United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Friedrich-Schiller-Universität Jena Germany (DE) University of Hawaii (U.H.) United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Universität Ulm Germany (DE) Fred Hutchinson Cancer Research Center Canada (CA) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Southern California (USC) United States (USA) (US) Institute for Oncology Ljubljana (OIL) Slovenia (SI) Dartmouth College United States (USA) (US) University of Cambridge United Kingdom (GB) University College London (UCL) United Kingdom (GB) University of California Irvine United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Yale University United States (USA) (US) Mount Sinai Hospital (MSH) Canada (CA) Stanford University United States (USA) (US) University of Glasgow United Kingdom (GB) Glasgow Royal Infirmary (GRI) United Kingdom (GB) Princess Anne Hospital United Kingdom (GB)

How to cite

APA:

Lee, A.W., Tyrer, J.P., Doherty, J.A., Stram, D.A., Kupryjanczyk, J., Dansonka-Mieszkowska, A.,... Pearce, C.L. (2015). Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study. Gynecologic Oncology, 136(3), 542-8. https://dx.doi.org/10.1016/j.ygyno.2014.12.017

MLA:

Lee, Alice W., et al. "Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study." Gynecologic Oncology 136.3 (2015): 542-8.

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