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; 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; Estrid Hogdall; Susanne K Kjaer; Lotte Nedergaard; Lene Lundvall; Claus Hogdall; Australian Cancer Study (Ovarian Cancer)

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, 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, Estrid Hogdall, Susanne K Kjaer, Lotte Nedergaard, Lene Lundvall, Claus Hogdall, Australian Cancer Study (Ovarian Cancer)

16 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Gynecologic Oncology
Vol/bind	136
Sider (fra-til)	542-548
ISSN	0090-8258
DOI	https://doi.org/10.1016/j.ygyno.2014.12.017
Status	Udgivet - 2015

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10.1016/j.ygyno.2014.12.017

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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., ... Australian Cancer Study (Ovarian Cancer) (2015). Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study. Gynecologic Oncology, 136, 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, 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, Hogdall, E , Kjaer, SK, Nedergaard, L, Lundvall, L, Hogdall, C & Australian Cancer Study (Ovarian Cancer) 2015, 'Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study', Gynecologic Oncology, bind 136, s. 542-548. https://doi.org/10.1016/j.ygyno.2014.12.017

@article{f82c3de7b10a4fdeb865680b6c330b6c,

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.",

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 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 Estrid Hogdall and Kjaer, {Susanne K} and Lotte Nedergaard and Lene Lundvall and Claus Hogdall and {Australian Cancer Study (Ovarian Cancer)}",

note = "Copyright {\textcopyright} 2014. Published by Elsevier Inc.",

year = "2015",

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

language = "English",

volume = "136",

pages = "542--548",

journal = "Gynecologic Oncology",

issn = "0090-8258",

publisher = "Academic Press Inc.",

}

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, 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 - Hogdall, Estrid

AU - Kjaer, Susanne K

AU - Nedergaard, Lotte

AU - Lundvall, Lene

AU - Hogdall, Claus

AU - Australian Cancer Study (Ovarian Cancer)

PY - 2015

Y1 - 2015

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.

U2 - 10.1016/j.ygyno.2014.12.017

DO - 10.1016/j.ygyno.2014.12.017

M3 - Journal article

C2 - 25528498

SN - 0090-8258

VL - 136

SP - 542

EP - 548

JO - Gynecologic Oncology

JF - Gynecologic Oncology

ER -

Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study

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