Format

Send to

Choose Destination
Hum Genet. 2016 Jul;135(7):741-56. doi: 10.1007/s00439-016-1663-9. Epub 2016 Apr 13.

Assessing the genetic architecture of epithelial ovarian cancer histological subtypes.

Cuellar-Partida G1,2, Lu Y3, Dixon SC4,5; Australian Ovarian Cancer Study, Fasching PA6,7, Hein A7, Burghaus S7, Beckmann MW7, Lambrechts D8,9, Van Nieuwenhuysen E10, Vergote I10, Vanderstichele A10, Doherty JA11, Rossing MA12,13, Chang-Claude J14,15, Rudolph A14, Wang-Gohrke S16, Goodman MT17,18, Bogdanova N19, Dörk T20, Dürst M21, Hillemanns P22, Runnebaum IB21, Antonenkova N23, Butzow R24, Leminen A25, Nevanlinna H25, Pelttari LM25, Edwards RP26,27, Kelley JL26, Modugno F26,27,28, Moysich KB29, Ness RB30, Cannioto R29, Høgdall E31,32, Høgdall C33, Jensen A31, Giles GG34,35,36, Bruinsma F36, Kjaer SK31,33, Hildebrandt MA37, Liang D38, Lu KH39, Wu X37, Bisogna M40, Dao F40, Levine DA40, Cramer DW41, Terry KL41,42, Tworoger SS42,43, Stampfer M42,43, Missmer S41,42,43, Bjorge L44,45, Salvesen HB44,45, Kopperud RK44,45, Bischof K44,45, Aben KK46,47, Kiemeney LA46, Massuger LF48, Brooks-Wilson A49,50, Olson SH51, McGuire V52, Rothstein JH52, Sieh W52, Whittemore AS52, Cook LS53, Le ND54, Blake Gilks C55, Gronwald J56, Jakubowska A56, Lubiński J56, Kluz T57, Song H58, Tyrer JP58, Wentzensen N59, Brinton L59, Trabert B59, Lissowska J60, McLaughlin JR61, Narod SA62, Phelan C63, Anton-Culver H64,65, Ziogas A64, Eccles D66, Campbell I67, Gayther SA68, Gentry-Maharaj A69, Menon U69, Ramus SJ68, Wu AH68, Dansonka-Mieszkowska A70, Kupryjanczyk J70, Timorek A71, Szafron L70, Cunningham JM72, Fridley BL73, Winham SJ74, Bandera EV75, Poole EM43, Morgan TK76,77, Goode EL78, Schildkraut JM79, Pearce CL68,80, Berchuck A81, Pharoah PD82,58, Webb PM4,5, Chenevix-Trench G83, Risch HA84, MacGregor S85.

Author information

1
Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia. gabriel.cuellar@qimrberghofer.edu.au.
2
School of Medicine, University of Queensland, St Lucia, QLD, 4072, Australia. gabriel.cuellar@qimrberghofer.edu.au.
3
Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
4
Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
5
School of Public Health, University of Queensland, Herston, QLD 4006, Australia.
6
Division of Hematology and Oncology, Department of Medicine, University of California at Los Angeles, David Geffen School of Medicine, Los Angeles, USA.
7
Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, University Hospital Erlangen, Universitaetsstrasse 21-23, 91054, Erlangen, Germany.
8
Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.
9
Vesalius Research Center, VIB, Louvain, Belgium.
10
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Louvain, Belgium.
11
Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA.
12
Department of Epidemiology, University of Washington, Seattle, WA, USA.
13
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
14
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
15
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
16
Department of Obstetrics and Gynecology, University of Ulm, Ulm, Germany.
17
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
18
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Community and Population Health Research Institute, Los Angeles, CA, USA.
19
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
20
Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
21
Department of Gynecology, Jena-University Hospital-Friedrich Schiller University, Jena, Germany.
22
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
23
N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus.
24
Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
25
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
26
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
27
Womens Cancer Research Program, Magee-Womens Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
28
Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
29
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
30
The University of Texas School of Public Health, Houston, TX, USA.
31
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
32
Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
33
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
34
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
35
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
36
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
37
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
38
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
39
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
40
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
41
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
42
Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.
43
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
44
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway.
45
Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway.
46
Radboud University Medical Centre, RADBOUD Institute for Health Sciences, Nijmegen, The Netherlands.
47
Netherlands Comprehensive Cancer Organisation, Utrecht, The Netherlands.
48
Department of Obstetrics and Gynaecology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
49
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
50
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC, Canada.
51
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
52
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
53
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
54
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
55
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
56
Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.
57
Faculty of Medicine, Institute of Midwifery and Emergency Medicine, Clinic of Obstetrics and Gynecology, Frederick Chopin Clinical Provincial Hospital No 1, University of Rzeszów, Rzeszow, Poland.
58
Department of Oncology, The Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
59
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
60
Department of Cancer Epidemiology and Prevention, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
61
Public Health Ontario, Toronto, ON, Canada.
62
Women's College Research Institute, University of Toronto, Toronto, ON, Canada.
63
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
64
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
65
Center for Cancer Genetics Research and Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA.
66
Faculty of Medicine, University of Southampton, Southampton, UK.
67
Research Division, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Australia.
68
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
69
Women's Cancer, Institute for Women's Health, University College London, London, UK.
70
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
71
Department of Obstetrics, Gynaecology and Oncology, IInd Faculty of Medicine, Warsaw Medical University and Brodnowski Hospital, Warsaw, Poland.
72
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
73
Department of Biostatistics, University of Kansas, Kansas City, KS, USA.
74
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
75
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
76
Department of Pathology and Obstetrics, OHSU, Portland, OR, USA.
77
Department of Gynaecology, OHSU, Portland, OR, USA.
78
Division of Epidemiology, Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
79
Department of Public Health Sciences, University of Virginia, Virginia, USA.
80
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA.
81
Duke Cancer Institute, Duke University Medical Center, Durham, NC, USA.
82
Department of Public Health and Primary Care, The Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
83
Cancer Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia.
84
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
85
Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, QLD, 4006, Australia. Stuart.MacGregor@qimrberghofer.edu.au.

Abstract

Epithelial ovarian cancer (EOC) is one of the deadliest common cancers. The five most common types of disease are high-grade and low-grade serous, endometrioid, mucinous and clear cell carcinoma. Each of these subtypes present distinct molecular pathogeneses and sensitivities to treatments. Recent studies show that certain genetic variants confer susceptibility to all subtypes while other variants are subtype-specific. Here, we perform an extensive analysis of the genetic architecture of EOC subtypes. To this end, we used data of 10,014 invasive EOC patients and 21,233 controls from the Ovarian Cancer Association Consortium genotyped in the iCOGS array (211,155 SNPs). We estimate the array heritability (attributable to variants tagged on arrays) of each subtype and their genetic correlations. We also look for genetic overlaps with factors such as obesity, smoking behaviors, diabetes, age at menarche and height. We estimated the array heritabilities of high-grade serous disease ([Formula: see text] = 8.8 ± 1.1 %), endometrioid ([Formula: see text] = 3.2 ± 1.6 %), clear cell ([Formula: see text] = 6.7 ± 3.3 %) and all EOC ([Formula: see text] = 5.6 ± 0.6 %). Known associated loci contributed approximately 40 % of the total array heritability for each subtype. The contribution of each chromosome to the total heritability was not proportional to chromosome size. Through bivariate and cross-trait LD score regression, we found evidence of shared genetic backgrounds between the three high-grade subtypes: serous, endometrioid and undifferentiated. Finally, we found significant genetic correlations of all EOC with diabetes and obesity using a polygenic prediction approach.

PMID:
27075448
PMCID:
PMC4976079
DOI:
10.1007/s00439-016-1663-9
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Supplementary concept, Grant support

Publication types

MeSH terms

Supplementary concept

Grant support

Supplemental Content

Full text links

Icon for Springer Icon for PubMed Central
Loading ...
Support Center