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 | |
| State | Published - Mar 1 2015 |
Keywords
- Gene
- Genetic variation
- Genetics
- Gonadotropins
- Ovarian cancer
- Polymorphisms
ASJC Scopus subject areas
- Oncology
- Obstetrics and Gynecology
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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 journal › Article › peer-review
}
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 ).
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
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 -