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Gynecol Oncol. 2015 Mar;136(3):542-8. doi: 10.1016/j.ygyno.2014.12.017. Epub 2014 Dec 17.

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

Lee AW1, Tyrer JP2, Doherty JA3, Stram DA1, Kupryjanczyk J4, Dansonka-Mieszkowska A4, Plisiecka-Halasa J4, Spiewankiewicz B5, Myers EJ1; Australian Cancer Study (Ovarian Cancer); Australian Ovarian Cancer Study Group, Chenevix-Trench G6, Fasching PA7, Beckmann MW8, Ekici AB9, Hein A8, Vergote I10, Van Nieuwenhuysen E10, Lambrechts D11, Wicklund KG12, Eilber U13, Wang-Gohrke S14, Chang-Claude J13, Rudolph A13, Sucheston-Campbell L15, Odunsi K16, Moysich KB15, Shvetsov YB17, Thompson PJ18, Goodman MT18, Wilkens LR17, Dörk T19, Hillemanns P20, Dürst M21, Runnebaum IB21, Bogdanova N19, Pelttari LM22, Nevanlinna H22, Leminen A22, Edwards RP23, Kelley JL24, Harter P25, Schwaab I26, Heitz F25, du Bois A25, Orsulic S27, Lester J27, Walsh C27, Karlan BY27, Hogdall E28, Kjaer SK29, Jensen A30, Vierkant RA31, Cunningham JM32, Goode EL31, Fridley BL33, Southey MC34, Giles GG35, Bruinsma F36, Wu X37, Hildebrandt MA37, Lu K38, Liang D39, Bisogna M40, Levine DA40, Weber RP41, Schildkraut JM42, Iversen ES43, Berchuck A44, Terry KL45, Cramer DW45, Tworoger SS46, Poole EM46, Olson SH47, Orlow I47, Bandera EV48, Bjorge L49, Tangen IL49, Salvesen HB49, Krakstad C49, Massuger LF50, Kiemeney LA51, Aben KK52, van Altena AM50, Bean Y53, Pejovic T53, Kellar M53, Le ND54, Cook LS55, Kelemen LE56, Brooks-Wilson A57, Lubinski J58, Gronwald J58, Cybulski C58, Jakubowska A58, Wentzensen N59, Brinton LA59, Lissowska J60, Yang H59, Nedergaard L61, Lundvall L62, Hogdall C62, Song H2, Campbell IG63, Eccles D64, Glasspool R65, Siddiqui N66, Carty K65, Paul J65, McNeish IA67, Sieh W68, McGuire V68, Rothstein JH68, Whittemore AS68, McLaughlin JR69, Risch HA70, Phelan CM71, Anton-Culver H72, Ziogas A73, Menon U74, Ramus SJ1, Gentry-Maharaj A74, Harrington P75, Pike MC76, Modugno F77, Rossing MA78, Ness RB79, Pharoah PD80, Stram DO1, Wu AH1, Pearce CL81.

Author information

1
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
2
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
3
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA.
4
Department of Pathology, Institute of Oncology, Warsaw, Poland.
5
Department of Gynecologic Oncology, Institute of Oncology, Warsaw, Poland.
6
Cancer Division, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
7
University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, Los Angeles, CA, USA; University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
8
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
9
University Hospital Erlangen, Institute of Human Genetics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
10
Division of Gynecological Oncology, Department of Oncology, University Hospitals Leuven, Belgium.
11
Vesalius Research Center, VIB, Leuven, Belgium; Laboratory for Translational Genetics, Vesalius Research Center, VIB and KU Leuven, Belgium.
12
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
13
German Cancer Research Center (DKFZ), Division of Cancer Epidemiology, Heidelberg, Germany.
14
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
15
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
16
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
17
Cancer Epidemiology Program, University of Hawaii Cancer Center, HI, USA.
18
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Community and Population Health Research Institute, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
19
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
20
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
21
Department of Gynecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany.
22
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, HUS, Finland.
23
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Ovarian Cancer Center of Excellence, University of Pittsburgh, Pittsburgh, PA, USA.
24
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
25
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, Essen, Germany; Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
26
Institut für Humangenetik Wiesbaden, Wiesbaden, Germany.
27
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
28
Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
29
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
30
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
31
Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
32
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
33
Biostatistics and Informatics Shared Resource, University of Kansas Medical Center, Kansas City, KS, USA.
34
Department of Pathology, University of Melbourne, Parkville, VIC Australia.
35
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
36
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
37
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
38
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
39
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
40
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
41
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA.
42
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA; Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
43
Department of Statistical Science, Duke University, Durham, NC, USA.
44
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
45
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
46
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
47
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
48
Cancer Prevention and Control, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
49
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway; Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
50
Department of Gynaecology, Radboud University Medical Centre, Nijmegen, The Netherlands.
51
Department for Health Evidence and Department of Urology, Radboud University Medical Centre, Nijmegen, The Netherlands.
52
Department for Health Evidence, Radboud University Medical Centre, Nijmegen, The Netherlands; Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands.
53
Department of Obstetrics and Gynecology, Oregon Health and Science University, Portland, OR, USA; Knight Cancer Institute, Portland, OR, USA.
54
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
55
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
56
Alberta Health Services-Cancer Care, Department of Population Health Research, Calgary, AB, Canada; Departments of Medical Genetics and Oncology, University of Calgary, Calgary, AB, Canada.
57
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC Canada.
58
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
59
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
60
Department of Cancer Epidemiology and Prevention, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
61
Deptartment of Pathology, Rigshospitalet, University of Copenhagen, Denmark.
62
Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
63
Department of Pathology, University of Melbourne, Parkville, VIC Australia; Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia.
64
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.
65
Cancer Research UK Clinical Trials Unit, Glasgow, The Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK.
66
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK.
67
Institute of Cancer Sciences, University of Glasgow, Wolfson Wohl Cancer Research Centre, Beatson Institute for Cancer Research, Glasgow, UK.
68
Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
69
Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
70
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
71
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
72
Department of Epidemiology, Genetic Epidemiology Research Institute, School of Medicine, University of California Irvine, Irvine, CA, USA.
73
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
74
Women's Cancer, Institute for Women's Health, University College London, London, UK.
75
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
76
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
77
Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA; Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
78
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA.
79
The University of Texas School of Public Health, Houston, TX, USA.
80
Department of Oncology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
81
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. Electronic address: lpearce@umich.edu.

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

PMID:
25528498
PMCID:
PMC4892108
DOI:
10.1016/j.ygyno.2014.12.017
[Indexed for MEDLINE]
Free PMC Article

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