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

Publication ,  Journal Article
Lee, AW; Tyrer, JP; Doherty, JA; Stram, DA; Kupryjanczyk, J; Dansonka-Mieszkowska, A; Plisiecka-Halasa, J; Spiewankiewicz, B; Myers, EJ; Hein, A ...
Published in: Gynecol Oncol
March 2015

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.

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Published In

Gynecol Oncol

DOI

EISSN

1095-6859

Publication Date

March 2015

Volume

136

Issue

3

Start / End Page

542 / 548

Location

United States

Related Subject Headings

  • Signal Transduction
  • Risk Factors
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Logistic Models
  • Humans
  • Gonadotropins
  • Genotype
  • Genome-Wide Association Study
 

Citation

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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. Gynecol Oncol, 136(3), 542–548. https://doi.org/10.1016/j.ygyno.2014.12.017
Lee, Alice W., Jonathan P. Tyrer, Jennifer A. Doherty, Douglas A. Stram, Jolanta Kupryjanczyk, Agnieszka Dansonka-Mieszkowska, Joanna Plisiecka-Halasa, et al. “Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.Gynecol Oncol 136, no. 3 (March 2015): 542–48. https://doi.org/10.1016/j.ygyno.2014.12.017.
Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, et al. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study. Gynecol Oncol. 2015 Mar;136(3):542–8.
Lee, Alice W., et al. “Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study.Gynecol Oncol, vol. 136, no. 3, Mar. 2015, pp. 542–48. Pubmed, doi:10.1016/j.ygyno.2014.12.017.
Lee AW, Tyrer JP, Doherty JA, Stram DA, Kupryjanczyk J, Dansonka-Mieszkowska A, Plisiecka-Halasa J, Spiewankiewicz B, Myers EJ, Australian Cancer Study (Ovarian Cancer), Australian Ovarian Cancer Study Group, Chenevix-Trench G, Fasching PA, Beckmann MW, 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, Dörk T, Hillemanns P, Dürst 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 IA, 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. Evaluating the ovarian cancer gonadotropin hypothesis: a candidate gene study. Gynecol Oncol. 2015 Mar;136(3):542–548.
Journal cover image

Published In

Gynecol Oncol

DOI

EISSN

1095-6859

Publication Date

March 2015

Volume

136

Issue

3

Start / End Page

542 / 548

Location

United States

Related Subject Headings

  • Signal Transduction
  • Risk Factors
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Logistic Models
  • Humans
  • Gonadotropins
  • Genotype
  • Genome-Wide Association Study