Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

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

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)542-548
Number of pages7
JournalGynecologic Oncology
Volume136
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Gonadotropins
Ovarian Neoplasms
Genes
Single Nucleotide Polymorphism
Genome
Penetrance
Genome-Wide Association Study
Sample Size
Prostatic Neoplasms
Logistic Models
Alleles
Genotype
Hormones
Breast Neoplasms

Keywords

  • Gene
  • Genetic variation
  • Genetics
  • Gonadotropins
  • Ovarian cancer
  • Polymorphisms

ASJC Scopus subject areas

  • Obstetrics and Gynecology
  • Oncology

Cite this

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), 542-548. https://doi.org/10.1016/j.ygyno.2014.12.017

Evaluating the ovarian cancer gonadotropin hypothesis : A candidate gene study. / 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.; 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.

In: Gynecologic Oncology, Vol. 136, No. 3, 01.03.2015, p. 542-548.

Research output: Contribution to journalArticle

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, 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 2015, 'Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study', Gynecologic Oncology, vol. 136, no. 3, pp. 542-548. 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. Gynecologic Oncology. 2015 Mar 1;136(3):542-548. https://doi.org/10.1016/j.ygyno.2014.12.017
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. ; 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. / Evaluating the ovarian cancer gonadotropin hypothesis : A candidate gene study. In: Gynecologic Oncology. 2015 ; Vol. 136, No. 3. pp. 542-548.
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title = "Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study",
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.",
keywords = "Gene, Genetic variation, Genetics, Gonadotropins, Ovarian cancer, Polymorphisms",
author = "Lee, {Alice W.} and Tyrer, {Jonathan P.} and Doherty, {Jennifer A.} and Stram, {Douglas A.} and Jolanta Kupryjanczyk and Agnieszka Dansonka-Mieszkowska and Joanna Plisiecka-Halasa and Beata Spiewankiewicz and Myers, {Emily J.} and Georgia Chenevix-Trench and Fasching, {Peter A.} and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Alexander Hein and Ignace Vergote and {Van Nieuwenhuysen}, Els and Diether Lambrechts and Wicklund, {Kristine G.} and Ursula Eilber and Shan Wang-Gohrke and Jenny Chang-Claude and Anja Rudolph and Lara Sucheston-Campbell and Kunle Odunsi and Moysich, {Kirsten B.} and Shvetsov, {Yurii B.} and Thompson, {Pamela J.} and Goodman, {Marc T.} and Wilkens, {Lynne R.} and Thilo D{\"o}rk and Peter Hillemanns and Matthias D{\"u}rst and Runnebaum, {Ingo B.} and Natalia Bogdanova and Pelttari, {Liisa M.} and Heli Nevanlinna and Arto Leminen and Edwards, {Robert P.} and Kelley, {Joseph L.} and Philipp Harter and Ira Schwaab and Florian Heitz and {Du Bois}, Andreas and Sandra Orsulic and Jenny Lester and Christine Walsh and Karlan, {Beth Y.} and Estrid Hogdall and Kjaer, {Susanne K.} and Allan Jensen and Vierkant, {Robert A.} and Cunningham, {Julie M} and Goode, {Ellen L} and Fridley, {Brooke L.} and Southey, {Melissa C.} and Giles, {Graham G.} and Fiona Bruinsma and Xifeng Wu and Hildebrandt, {Michelle A T} and Karen Lu and Dong Liang and Maria Bisogna and Levine, {Douglas A.} and Weber, {Rachel Palmieri} and Schildkraut, {Joellen M.} and Iversen, {Edwin S.} and Andrew Berchuck and Terry, {Kathryn L.} and Cramer, {Daniel W.} and Tworoger, {Shelley S.} and Poole, {Elizabeth M.} and Olson, {Sara H.} and Irene Orlow and Bandera, {Elisa V.} and Line Bjorge and Tangen, {Ingvild L.} and Salvesen, {Helga B.} and Camilla Krakstad and Massuger, {Leon F A G} and Kiemeney, {Lambertus A.} and Aben, {Katja K H} and {Van Altena}, {Anne M.} and Yukie Bean and Tanja Pejovic and Melissa Kellar and Le, {Nhu D.} and Cook, {Linda S.} and Kelemen, {Linda E.} and Angela Brooks-Wilson and Jan Lubinski and Jacek Gronwald and Cezary Cybulski and Anna Jakubowska and Nicolas Wentzensen and Brinton, {Louise A.} and Jolanta Lissowska and Hannah Yang and Lotte Nedergaard and Lene Lundvall and Claus Hogdall and Honglin Song and Campbell, {Ian G.} and Diana Eccles and Rosalind Glasspool and Nadeem Siddiqui and Karen Carty and James Paul and McNeish, {Iain A.} and Weiva Sieh and Valerie McGuire and Rothstein, {Joseph H.} and Whittemore, {Alice S.} and McLaughlin, {John R.} and Risch, {Harvey A.} and Phelan, {Catherine M.} and Hoda Anton-Culver and Argyrios Ziogas and Usha Menon and Ramus, {Susan J.} and Aleksandra Gentry-Maharaj and Patricia Harrington and Pike, {Malcolm C.} and Francesmary Modugno and Rossing, {Mary Anne} and Ness, {Roberta B.} and Pharoah, {Paul D P} and Stram, {Daniel O.} and Wu, {Anna H.} and Pearce, {Celeste Leigh}",
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doi = "10.1016/j.ygyno.2014.12.017",
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pages = "542--548",
journal = "Gynecologic Oncology",
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}

TY - JOUR

T1 - Evaluating the ovarian cancer gonadotropin hypothesis

T2 - A candidate gene study

AU - Lee, Alice W.

AU - Tyrer, Jonathan P.

AU - Doherty, Jennifer A.

AU - Stram, Douglas A.

AU - Kupryjanczyk, Jolanta

AU - Dansonka-Mieszkowska, Agnieszka

AU - Plisiecka-Halasa, Joanna

AU - Spiewankiewicz, Beata

AU - Myers, Emily J.

AU - Chenevix-Trench, Georgia

AU - Fasching, Peter A.

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Hein, Alexander

AU - Vergote, Ignace

AU - Van Nieuwenhuysen, Els

AU - Lambrechts, Diether

AU - Wicklund, Kristine G.

AU - Eilber, Ursula

AU - Wang-Gohrke, Shan

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Sucheston-Campbell, Lara

AU - Odunsi, Kunle

AU - Moysich, Kirsten B.

AU - Shvetsov, Yurii B.

AU - Thompson, Pamela J.

AU - Goodman, Marc T.

AU - Wilkens, Lynne R.

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo B.

AU - Bogdanova, Natalia

AU - Pelttari, Liisa M.

AU - Nevanlinna, Heli

AU - Leminen, Arto

AU - Edwards, Robert P.

AU - Kelley, Joseph L.

AU - Harter, Philipp

AU - Schwaab, Ira

AU - Heitz, Florian

AU - Du Bois, Andreas

AU - Orsulic, Sandra

AU - Lester, Jenny

AU - Walsh, Christine

AU - Karlan, Beth Y.

AU - Hogdall, Estrid

AU - Kjaer, Susanne K.

AU - Jensen, Allan

AU - Vierkant, Robert A.

AU - Cunningham, Julie M

AU - Goode, Ellen L

AU - Fridley, Brooke L.

AU - Southey, Melissa C.

AU - Giles, Graham G.

AU - Bruinsma, Fiona

AU - Wu, Xifeng

AU - Hildebrandt, Michelle A T

AU - Lu, Karen

AU - Liang, Dong

AU - Bisogna, Maria

AU - Levine, Douglas A.

AU - Weber, Rachel Palmieri

AU - Schildkraut, Joellen M.

AU - Iversen, Edwin S.

AU - Berchuck, Andrew

AU - Terry, Kathryn L.

AU - Cramer, Daniel W.

AU - Tworoger, Shelley S.

AU - Poole, Elizabeth M.

AU - Olson, Sara H.

AU - Orlow, Irene

AU - Bandera, Elisa V.

AU - Bjorge, Line

AU - Tangen, Ingvild L.

AU - Salvesen, Helga B.

AU - Krakstad, Camilla

AU - Massuger, Leon F A G

AU - Kiemeney, Lambertus A.

AU - Aben, Katja K H

AU - Van Altena, Anne M.

AU - Bean, Yukie

AU - Pejovic, Tanja

AU - Kellar, Melissa

AU - Le, Nhu D.

AU - Cook, Linda S.

AU - Kelemen, Linda E.

AU - Brooks-Wilson, Angela

AU - Lubinski, Jan

AU - Gronwald, Jacek

AU - Cybulski, Cezary

AU - Jakubowska, Anna

AU - Wentzensen, Nicolas

AU - Brinton, Louise A.

AU - Lissowska, Jolanta

AU - Yang, Hannah

AU - Nedergaard, Lotte

AU - Lundvall, Lene

AU - Hogdall, Claus

AU - Song, Honglin

AU - Campbell, Ian G.

AU - Eccles, Diana

AU - Glasspool, Rosalind

AU - Siddiqui, Nadeem

AU - Carty, Karen

AU - Paul, James

AU - McNeish, Iain A.

AU - Sieh, Weiva

AU - McGuire, Valerie

AU - Rothstein, Joseph H.

AU - Whittemore, Alice S.

AU - McLaughlin, John R.

AU - Risch, Harvey A.

AU - Phelan, Catherine M.

AU - Anton-Culver, Hoda

AU - Ziogas, Argyrios

AU - Menon, Usha

AU - Ramus, Susan J.

AU - Gentry-Maharaj, Aleksandra

AU - Harrington, Patricia

AU - Pike, Malcolm C.

AU - Modugno, Francesmary

AU - Rossing, Mary Anne

AU - Ness, Roberta B.

AU - Pharoah, Paul D P

AU - Stram, Daniel O.

AU - Wu, Anna H.

AU - Pearce, Celeste Leigh

PY - 2015/3/1

Y1 - 2015/3/1

N2 - 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.

AB - 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.

KW - Gene

KW - Genetic variation

KW - Genetics

KW - Gonadotropins

KW - Ovarian cancer

KW - Polymorphisms

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UR - http://www.scopus.com/inward/citedby.url?scp=84924262838&partnerID=8YFLogxK

U2 - 10.1016/j.ygyno.2014.12.017

DO - 10.1016/j.ygyno.2014.12.017

M3 - Article

C2 - 25528498

AN - SCOPUS:84924262838

VL - 136

SP - 542

EP - 548

JO - Gynecologic Oncology

JF - Gynecologic Oncology

SN - 0090-8258

IS - 3

ER -