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Hum Mol Genet. 2015 Oct 15;24(20):5955-64. doi: 10.1093/hmg/ddv306. Epub 2015 Jul 30.

Shared genetics underlying epidemiological association between endometriosis and ovarian cancer.

Lu Y1, Cuellar-Partida G1, Painter JN2, Nyholt DR3; Australian Ovarian Cancer Study; International Endogene Consortium (IEC), Morris AP4, Fasching PA5, Hein A6, Burghaus S6, Beckmann MW6, Lambrechts D7, Van Nieuwenhuysen E8, Vergote I8, Vanderstichele A8, Doherty JA9, Rossing MA10, Wicklund KG11, Chang-Claude J12, Eilber U12, Rudolph A12, Wang-Gohrke S13, Goodman MT14, Bogdanova N15, Dörk T16, Dürst M17, Hillemanns P18, Runnebaum IB17, Antonenkova N19, Butzow R20, Leminen A21, Nevanlinna H21, Pelttari LM21, Edwards RP22, Kelley JL23, Modugno F24, Moysich KB25, Ness RB26, Cannioto R25, Høgdall E27, Jensen A28, Giles GG29, Bruinsma F30, Kjaer SK31, Hildebrandt MA32, Liang D33, Lu KH34, Wu X32, Bisogna M35, Dao F35, Levine DA35, Cramer DW36, Terry KL37, Tworoger SS38, Missmer S39, Bjorge L40, Salvesen HB40, Kopperud RK40, Bischof K40, Aben KK41, Kiemeney LA42, Massuger LF43, Brooks-Wilson A44, Olson SH45, McGuire V46, Rothstein JH46, Sieh W46, Whittemore AS46, Cook LS47, Le ND48, Gilks CB49, Gronwald J50, Jakubowska A50, Lubiński J50, Gawełko J51, Song H52, Tyrer JP52, Wentzensen N53, Brinton L53, Trabert B53, Lissowska J54, Mclaughlin JR55, Narod SA56, Phelan C57, Anton-Culver H58, Ziogas A32, Eccles D59, Gayther SA60, Gentry-Maharaj A61, Menon U61, Ramus SJ60, Wu AH60, Dansonka-Mieszkowska A62, Kupryjanczyk J62, Timorek A63, Szafron L62, Cunningham JM64, Fridley BL65, Winham SJ66, Bandera EV67, Poole EM38, Morgan TK68, Risch HA69, Goode EL70, Schildkraut JM71, Webb PM72, Pearce CL73, Berchuck A74, Pharoah PD75, Montgomery GW76, Zondervan KT77, Chenevix-Trench G78, MacGregor S79.

Author information

1
Statistical Genetics.
2
Molecular Cancer Epidemiology.
3
Institute of Health and Biomedical Innovation, Queensland University of Technology, Queensland, Australia.
4
Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics and Department of Biostatistics, University of Liverpool, Liverpool, UK.
5
Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
6
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Universitaetsstrasse 21-23, 91054 Erlangen, Germany.
7
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium, Vesalius Research Center, VIB, Leuven, Belgium.
8
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
9
Department of Community and Family Medicine, Section of Biostatistics & Epidemiology, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
10
Department of Epidemiology, University of Washington, Seattle, WA, USA, Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
11
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
12
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
13
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
14
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
15
Radiation Oncology Research Unit.
16
Gynaecology Research Unit and.
17
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.
18
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
19
N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.
20
Department of Pathology and.
21
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
22
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
23
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
24
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
25
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
26
The University of Texas School of Public Health, Houston, TX, USA.
27
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark, Molecular Unit, Department of Pathology, Herlev Hospital, Herlev, Denmark.
28
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
29
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia, Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
30
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
31
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark, Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
32
Department of Epidemiology and.
33
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
34
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
35
Gynecology Service, Department of Surgery and.
36
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
37
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
38
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Channing Division of Network Medicine, Department of Medicine and.
39
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Channing Division of Network Medicine, Department of Medicine and Department of Obstetrics and Gynecology, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
40
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway, Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
41
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, The Netherlands, Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
42
Radboud University Medical Centre, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
43
Department of Obstetrics and Gynaecology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
44
Canada's Michael Smith Genome Sciences Centre and Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
45
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
46
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
47
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
48
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
49
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
50
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
51
Medical Faculty, Institute of Nursing and Health Sciences, University of Rzeszów, Rzeszów, Poland.
52
Department of Oncology and.
53
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
54
M. Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland.
55
Public Health Ontario, Toronto, ON, Canada.
56
Women's College Research Institute, University of Toronto, Toronto, ON, Canada.
57
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
58
Department of Epidemiology and Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA.
59
Faculty of Medicine, University of Southampton, Southampton, UK.
60
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
61
Women's Cancer, Institute for Women's Health, University College London, London, UK.
62
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
63
Department of Obstetrics, Gynecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
64
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology.
65
Department of Biostatistics, University of Kansas, Kansas City, KS, USA.
66
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research and.
67
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
68
Department of Pathology and Department of Obstetrics and Gynecology, OHSU, Portland, OR, USA.
69
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
70
Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
71
Department of Community and Family Medicine and Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
72
Population Health Department.
73
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 and.
74
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
75
Department of Oncology and Department of Public Health and Primary Care, The Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
76
Molecular Epidemiology and.
77
Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics and Endometriosis CaRe Centre, Nuffield Dept of Obstetrics & Gynaecology, University of Oxford, Oxford, UK.
78
Genetics and Computational Biology Department, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD 4006, Australia.
79
Statistical Genetics, stuart.macgregor@qimrberghofer.edu.au.

Abstract

Epidemiological studies have demonstrated associations between endometriosis and certain histotypes of ovarian cancer, including clear cell, low-grade serous and endometrioid carcinomas. We aimed to determine whether the observed associations might be due to shared genetic aetiology. To address this, we used two endometriosis datasets genotyped on common arrays with full-genome coverage (3194 cases and 7060 controls) and a large ovarian cancer dataset genotyped on the customized Illumina Infinium iSelect (iCOGS) arrays (10 065 cases and 21 663 controls). Previous work has suggested that a large number of genetic variants contribute to endometriosis and ovarian cancer (all histotypes combined) susceptibility. Here, using the iCOGS data, we confirmed polygenic architecture for most histotypes of ovarian cancer. This led us to evaluate if the polygenic effects are shared across diseases. We found evidence for shared genetic risks between endometriosis and all histotypes of ovarian cancer, except for the intestinal mucinous type. Clear cell carcinoma showed the strongest genetic correlation with endometriosis (0.51, 95% CI = 0.18-0.84). Endometrioid and low-grade serous carcinomas had similar correlation coefficients (0.48, 95% CI = 0.07-0.89 and 0.40, 95% CI = 0.05-0.75, respectively). High-grade serous carcinoma, which often arises from the fallopian tubes, showed a weaker genetic correlation with endometriosis (0.25, 95% CI = 0.11-0.39), despite the absence of a known epidemiological association. These results suggest that the epidemiological association between endometriosis and ovarian adenocarcinoma may be attributable to shared genetic susceptibility loci.

PMID:
26231222
PMCID:
PMC4581608
DOI:
10.1093/hmg/ddv306
[Indexed for MEDLINE]
Free PMC Article

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