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-Gohrke; Jenny 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

doi:10.1016/j.ygyno.2014.12.017

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

Obstetrics & Gynecology

Research output: Contribution to journal › Article › peer-review

13 Scopus citations

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 language	English (US)
Pages (from-to)	542-548
Number of pages	7
Journal	Gynecologic oncology
Volume	136
Issue number	3
DOIs	https://doi.org/10.1016/j.ygyno.2014.12.017
State	Published - Mar 1 2015

Keywords

Gene
Genetic variation
Genetics
Gonadotropins
Ovarian cancer
Polymorphisms

ASJC Scopus subject areas

Oncology
Obstetrics and Gynecology

Access to Document

10.1016/j.ygyno.2014.12.017

Cite this

Lee, A. W., Tyrer, J. P., Doherty, J. A., Stram, D. A., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Spiewankiewicz, B., Myers, E. J., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Vergote, I., Van Nieuwenhuysen, E., Lambrechts, D., Wicklund, K. G., Eilber, U., ... 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

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

@article{edeb0c48452d4d5d9c8a063760f0df47,

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}",

note = "Funding Information: The scientific development and funding for this project were funded by the following: the US National Cancer Institute ( R01-CA076016 ); the COGS project is funded through a European Commission 's Seventh Framework Programme grant (agreement number 223175 HEALTH F2 2009-223175 ); the Genetic Associations and Mechanisms in Oncology (GAME‐ON) : a NCI Cancer Post-GWAS Initiative ( U19-CA148112 ); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith ( PPD/RPCI.07 ). Funding Information: Funding of the constituent studies was provided by the California Cancer Research Program ( 00-01389V-20170 , N01-CN25403 , 2II0200 ); the Canadian Institutes of Health Research ( MOP-86727 ); Cancer Council Victoria ( 211, 191 ); Cancer Council Queensland ( 211, 191 ); Cancer Council New South Wales ( 211, 191 ); Cancer Council South Australiax ( 211, 191 ); Cancer Council Tasmania ( 211, 182 ); Cancer Council of Western Australia ( 211, 182 ); the Cancer Institute of New Jersey ; Cancer Research UK ( C490/A6187 , C490/A10119 , C490/A10124 ); the Danish Cancer Society ( 94-222-52 ); the ELAN Program of the University of Erlangen-Nuremberg ; the Eve Appeal ; the Helsinki University Central Hospital Research Fund ; Helse Vest ( 911624 ); the Norwegian Cancer Society ( 628837 ); the Norwegian Research Council ( 205404 ); the Ovarian Cancer Research Fund ; Nationaal Kanker Plan of Belgium ( PNC.NKP_29_039 ); the L & S Milken Foundation ; the Polish Ministry of Science and Higher Education ( 4 PO5C 028 14 , 2 PO5A 068 27 ); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute ( K07-CA095666 , K07-CA143047 , K07-CA80668 , P50-CA159981 , K22-CA138563 , N01-CN55424 , N01-PC67001 , N01-PC067010 , N01-PC035137 , P01-CA017054 , P01-CA087696 , P30-CA072720 , P30-CA15083 , P30-CA008748 , P50-CA105009 , P50-CA136393 , R01-CA014089 , R01-CA016056 , R01-CA017054 , R01-CA049449 , R01-CA050385 , R01-CA054419 , R01-CA058598 , R01-CA058860 , R01-CA061107 , R01-CA061132 , R01-CA063678 , R01-CA063682 , R01-CA067262 , R01-CA071766 , R01-CA074850 , R01-CA080978 , R01-CA083918 , R01-CA087538 , R01-CA092044 , R01-095023 , R01-CA122443 , R01-CA112523 , R01-CA114343 , R01-CA126841 , R01-CA136924 , R03-CA113148 , R03-CA115195 , U01-CA069417 , U01-CA071966 and Intramural research funds); the US Army Medical Research and Material Command ( DAMD17-01-1-0729 , DAMD17-02-1-0666 , DAMD17-02-1-0669 , W81XWH-07-0449 , W81XWH-10-1-02802 ); the US Public Health Service ( PSA-042205 ); The National Health and Medical Research Council of Australia ( 400413 , 199600, and 400281 ); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research ( 01GB 9401 ); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm ( P.685 ); the Minnesota Ovarian Cancer Alliance ; the Mayo Foundation ; the Fred C. and Katherine B. Andersen Foundation ; the Lon V. Smith Foundation ( LVS-39420 ); the Oak Foundation ; the OHSU Foundation; the Mermaid I Project ; the Rudolf-Bartling Foundation ( IV/113 ); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London , University College Hospital “Women's Health Theme” and the Royal Marsden Hospital ; WorkSafeBC 14 . Funding Information: A.W.L. is supported by a T32 training grant from the National Institute of Environmental Health Sciences ( T32ES013678 ); G.C.T. is supported by the National Health and Medical Research Council ; B.K. holds an American Cancer Society Early Detection Professorship ( SIOP-06-258-01-COUN ); L.E.K. is supported by a Canadian Institutes of Health Research New Investigator Award ( MSH-87734 ). Publisher Copyright: {\textcopyright} 2014 Elsevier Inc. All rights reserved.",

year = "2015",

month = mar,

day = "1",

doi = "10.1016/j.ygyno.2014.12.017",

language = "English (US)",

volume = "136",

pages = "542--548",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

number = "3",

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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

N1 - Funding Information: The scientific development and funding for this project were funded by the following: the US National Cancer Institute ( R01-CA076016 ); the COGS project is funded through a European Commission 's Seventh Framework Programme grant (agreement number 223175 HEALTH F2 2009-223175 ); the Genetic Associations and Mechanisms in Oncology (GAME‐ON) : a NCI Cancer Post-GWAS Initiative ( U19-CA148112 ); the Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith ( PPD/RPCI.07 ). Funding Information: Funding of the constituent studies was provided by the California Cancer Research Program ( 00-01389V-20170 , N01-CN25403 , 2II0200 ); the Canadian Institutes of Health Research ( MOP-86727 ); Cancer Council Victoria ( 211, 191 ); Cancer Council Queensland ( 211, 191 ); Cancer Council New South Wales ( 211, 191 ); Cancer Council South Australiax ( 211, 191 ); Cancer Council Tasmania ( 211, 182 ); Cancer Council of Western Australia ( 211, 182 ); the Cancer Institute of New Jersey ; Cancer Research UK ( C490/A6187 , C490/A10119 , C490/A10124 ); the Danish Cancer Society ( 94-222-52 ); the ELAN Program of the University of Erlangen-Nuremberg ; the Eve Appeal ; the Helsinki University Central Hospital Research Fund ; Helse Vest ( 911624 ); the Norwegian Cancer Society ( 628837 ); the Norwegian Research Council ( 205404 ); the Ovarian Cancer Research Fund ; Nationaal Kanker Plan of Belgium ( PNC.NKP_29_039 ); the L & S Milken Foundation ; the Polish Ministry of Science and Higher Education ( 4 PO5C 028 14 , 2 PO5A 068 27 ); the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute ( K07-CA095666 , K07-CA143047 , K07-CA80668 , P50-CA159981 , K22-CA138563 , N01-CN55424 , N01-PC67001 , N01-PC067010 , N01-PC035137 , P01-CA017054 , P01-CA087696 , P30-CA072720 , P30-CA15083 , P30-CA008748 , P50-CA105009 , P50-CA136393 , R01-CA014089 , R01-CA016056 , R01-CA017054 , R01-CA049449 , R01-CA050385 , R01-CA054419 , R01-CA058598 , R01-CA058860 , R01-CA061107 , R01-CA061132 , R01-CA063678 , R01-CA063682 , R01-CA067262 , R01-CA071766 , R01-CA074850 , R01-CA080978 , R01-CA083918 , R01-CA087538 , R01-CA092044 , R01-095023 , R01-CA122443 , R01-CA112523 , R01-CA114343 , R01-CA126841 , R01-CA136924 , R03-CA113148 , R03-CA115195 , U01-CA069417 , U01-CA071966 and Intramural research funds); the US Army Medical Research and Material Command ( DAMD17-01-1-0729 , DAMD17-02-1-0666 , DAMD17-02-1-0669 , W81XWH-07-0449 , W81XWH-10-1-02802 ); the US Public Health Service ( PSA-042205 ); The National Health and Medical Research Council of Australia ( 400413 , 199600, and 400281 ); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research ( 01GB 9401 ); the State of Baden-Wurttemberg through Medical Faculty of the University of Ulm ( P.685 ); the Minnesota Ovarian Cancer Alliance ; the Mayo Foundation ; the Fred C. and Katherine B. Andersen Foundation ; the Lon V. Smith Foundation ( LVS-39420 ); the Oak Foundation ; the OHSU Foundation; the Mermaid I Project ; the Rudolf-Bartling Foundation ( IV/113 ); the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London , University College Hospital “Women's Health Theme” and the Royal Marsden Hospital ; WorkSafeBC 14 . Funding Information: A.W.L. is supported by a T32 training grant from the National Institute of Environmental Health Sciences ( T32ES013678 ); G.C.T. is supported by the National Health and Medical Research Council ; B.K. holds an American Cancer Society Early Detection Professorship ( SIOP-06-258-01-COUN ); L.E.K. is supported by a Canadian Institutes of Health Research New Investigator Award ( MSH-87734 ). Publisher Copyright: © 2014 Elsevier Inc. All rights reserved.

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

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

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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 -

Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

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