Title: Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.

Authors: Lee, Alice W; Tyrer, Jonathan P; Doherty, Jennifer A; Stram, Douglas A; Kupryjanczyk, Jolanta; Dansonka-Mieszkowska, Agnieszka; Plisiecka-Halasa, Joanna; Spiewankiewicz, Beata; Myers, Emily J; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group; Chenevix-Trench, Georgia; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Hein, Alexander; Vergote, Ignace; Van Nieuwenhuysen, Els; Lambrechts, Diether; Wicklund, Kristine G; Eilber, Ursula; Wang-Gohrke, Shan; Chang-Claude, Jenny; Rudolph, Anja; Sucheston-Campbell, Lara; Odunsi, Kunle; Moysich, Kirsten B; Shvetsov, Yurii B; Thompson, Pamela J; Goodman, Marc T; Wilkens, Lynne R; Dörk, Thilo; Hillemanns, Peter; Dürst, Matthias; Runnebaum, Ingo B; Bogdanova, Natalia; Pelttari, Liisa M; Nevanlinna, Heli; Leminen, Arto; Edwards, Robert P; Kelley, Joseph L; Harter, Philipp; Schwaab, Ira; Heitz, Florian; du Bois, Andreas; Orsulic, Sandra; Lester, Jenny; Walsh, Christine; Karlan, Beth Y; Hogdall, Estrid; Kjaer, Susanne K; Jensen, Allan; Vierkant, Robert A; Cunningham, Julie M; Goode, Ellen L; Fridley, Brooke L; Southey, Melissa C; Giles, Graham G; Bruinsma, Fiona; Wu, Xifeng; Hildebrandt, Michelle A T; Lu, Karen; Liang, Dong; Bisogna, Maria; Levine, Douglas A; Weber, Rachel Palmieri; Schildkraut, Joellen M; Iversen, Edwin S; Berchuck, Andrew; Terry, Kathryn L; Cramer, Daniel W; Tworoger, Shelley S; Poole, Elizabeth M; Olson, Sara H; Orlow, Irene; Bandera, Elisa V; Bjorge, Line; Tangen, Ingvild L; Salvesen, Helga B; Krakstad, Camilla; Massuger, Leon F A G; Kiemeney, Lambertus A; Aben, Katja K H; van Altena, Anne M; Bean, Yukie; Pejovic, Tanja; Kellar, Melissa; Le, Nhu D; Cook, Linda S; Kelemen, Linda E; Brooks-Wilson, Angela; Lubinski, Jan; Gronwald, Jacek; Cybulski, Cezary; Jakubowska, Anna; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Yang, Hannah; Nedergaard, Lotte; Lundvall, Lene; Hogdall, Claus; Song, Honglin; Campbell, Ian G; Eccles, Diana; Glasspool, Rosalind; Siddiqui, Nadeem; Carty, Karen; Paul, James; McNeish, Iain A; Sieh, Weiva; McGuire, Valerie; Rothstein, Joseph H; Whittemore, Alice S; McLaughlin, John R; Risch, Harvey A; Phelan, Catherine M; Anton-Culver, Hoda; Ziogas, Argyrios; Menon, Usha; Ramus, Susan J; Gentry-Maharaj, Aleksandra; Harrington, Patricia; Pike, Malcolm C; Modugno, Francesmary; Rossing, Mary Anne; Ness, Roberta B; Pharoah, Paul D P; Stram, Daniel O; Wu, Anna H; Pearce, Celeste Leigh

Published In Gynecol Oncol, (2015 Mar)

Abstract: OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

PubMed ID: 25528498

MeSH Terms: Biomarkers, Tumor/genetics*; Biomarkers, Tumor/metabolism; Case-Control Studies; Female; Genetic Markers; Genetic Predisposition to Disease*; Genome-Wide Association Study; Genotype; Gonadotropins/metabolism*; Humans; Logistic Models; Ovarian Neoplasms/genetics*; Ovarian Neoplasms/metabolism; Polymorphism, Single Nucleotide*; Risk Factors; Signal Transduction