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Int J Epidemiol. 2016 Jun;45(3):884-95. doi: 10.1093/ije/dyw158. Epub 2016 Jul 10.

Adult body mass index and risk of ovarian cancer by subtype: a Mendelian randomization study.

Dixon SC1, Nagle CM2, Thrift AP3, Pharoah PD4, Pearce CL5, Zheng W6, Painter JN7; AOCS Group & Australian Cancer Study (Ovarian Cancer), Chenevix-Trench G8, Fasching PA9, Beckmann MW10, Lambrechts D11, Vergote I12, Lambrechts S12, Van Nieuwenhuysen E12, Rossing MA13, Doherty JA14, Wicklund KG15, Chang-Claude J16, Rudolph A16, Moysich KB17, Odunsi K18, Goodman MT19, Wilkens LR20, Thompson PJ21, Shvetsov YB20, Dörk T22, Park-Simon TW22, Hillemanns P22, Bogdanova N23, Butzow R24, Nevanlinna H25, Pelttari LM25, Leminen A25, Modugno F26, Ness RB27, Edwards RP28, Kelley JL29, Heitz F30, Karlan BY31, Kjær SK32, Høgdall E33, Jensen A34, Goode EL35, Fridley BL36, Cunningham JM37, Winham SJ38, Giles GG39, Bruinsma F40, Milne RL41, Southey MC42, Hildebrandt MA43, Wu X43, Lu KH44, Liang D45, Levine DA46, Bisogna M46, Schildkraut JM47, Berchuck A48, Cramer DW49, Terry KL49, Bandera EV50, Olson SH51, Salvesen HB52, Thomsen LC52, Kopperud RK52, Bjorge L52, Kiemeney LA53, Massuger LF54, Pejovic T55, Cook LS56, Le ND57, Swenerton KD58, Brooks-Wilson A59, Kelemen LE60, Lubiński J61, Huzarski T61, Gronwald J61, Menkiszak J62, Wentzensen N63, Brinton L63, Yang H63, Lissowska J64, Høgdall CK65, Lundvall L65, Song H66, Tyrer JP66, Campbell I67, Eccles D68, Paul J69, Glasspool R69, Siddiqui N70, Whittemore AS71, Sieh W71, McGuire V71, Rothstein JH71, Narod SA72, Phelan C73, Risch HA74, McLaughlin JR75, Anton-Culver H76, Ziogas A77, Menon U78, Gayther SA79, Ramus SJ79, Gentry-Maharaj A78, Wu AH79, Pike MC51, Tseng CC79, Kupryjanczyk J80, Dansonka-Mieszkowska A80, Budzilowska A80, Spiewankiewicz B81, Webb PM2; Ovarian Cancer Association Consortium.

Author information

1
Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia The University of Queensland, School of Public Health, Brisbane, QLD, Australia Suzanne.Dixon@qimrberghofer.edu.au.
2
Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia The University of Queensland, School of Public Health, Brisbane, QLD, Australia.
3
Department of Medicine and Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
4
Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
5
Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
6
Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
7
Molecular Cancer Epidemiology Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
8
Cancer Genetics Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
9
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 Nuremberg, Erlangen, Germany.
10
University Hospital Erlangen, Department of Gynecology and Obstetrics, Friedrich-Alexander-University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen Nuremberg, Erlangen, Germany.
11
Vesalius Research Center, VIB, Leuven, Belgium Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Belgium.
12
Division of Gynecologic Oncology, Department of Obstetrics and Gynaecology and Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
13
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.
14
Department of Epidemiology, The Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
15
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
16
German Cancer Research Center, Division of Cancer Epidemiology, Heidelberg, Germany.
17
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
18
Department of Gynecological Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA.
19
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.
20
Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
21
Cancer Prevention and Control, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
22
Clinics of Obstetrics and Gynaecology, Hannover Medical School, Hannover, Germany.
23
Radiation Oncology Research Unit, Hannover Medical School, Hannover, Germany.
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 Ovarian Cancer Center of Excellence, Women's Cancer Research Program, Magee-Women's 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.
27
The University of Texas School of Public Health, Houston, TX, USA.
28
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Ovarian Cancer Center of Excellence, Women's Cancer Research Program, Magee-Women's Research Institute and University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
29
Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
30
Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang. Huyssens-Stiftung/ Knappschaft GmbH, Essen, Germany Department of Gynecology and Gynecologic Oncology, Dr. Horst Schmidt Kliniken Wiesbaden, Wiesbaden, Germany.
31
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
32
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
33
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark.
34
Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.
35
Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
36
University of Kansas Medical Center, Kansas City, KS, USA.
37
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
38
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA.
39
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, Melbourne, VIC, Australia Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia.
40
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.
41
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, Melbourne, VIC, Australia.
42
Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, VIC, Australia.
43
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
44
Department of Gynecologic Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
45
College of Pharmacy and Health Sciences, Texas Southern University, Houston, TX, USA.
46
Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
47
Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA Cancer Control and Population Sciences, Duke Cancer Institute, Durham, NC, USA.
48
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
49
Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Boston, MA, USA.
50
Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
51
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
52
Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway.
53
Radboud University Medical Center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
54
Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Department of Gynaecology, Nijmegen, The Netherlands.
55
Department of Obstetrics & Gynecology, Oregon Health & Science University, Portland, OR, USA Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
56
Division of Epidemiology and Biostatistics, Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA.
57
Cancer Control Research, BC Cancer Agency, Vancouver, BC, Canada.
58
Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
59
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.
60
Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA.
61
International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
62
Department of Gynecological Surgery and Gynecological Oncology of Adults and Adolescents, Pomeranian Medical University, Szczecin, Poland.
63
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
64
Department of Cancer Epidemiology and Prevention, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
65
Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
66
Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
67
Cancer Genetics Laboratory, Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia Department of Pathology, University of Melbourne, Parkville, VIC, Australia.
68
Faculty of Medicine, University of Southampton, Southampton, UK.
69
The Beatson West of Scotland Cancer Centre, Glasgow, UK.
70
Department of Gynaecological Oncology, Glasgow Royal Infirmary, Glasgow, UK.
71
Department of Health Research and Policy-Epidemiology, Stanford University School of Medicine, Stanford, CA, USA.
72
Women's College Research Institute, University of Toronto, Toronto, ON, Canada.
73
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
74
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
75
Public Health Ontario, Toronto, ON, Canada.
76
Department of Epidemiology, University of California Irvine, Irvine, CA, USA Genetic Epidemiology Research Institute, UCI Center for Cancer Genetics Research & Prevention, School of Medicine, University of California Irvine, Irvine, CA, USA.
77
Department of Epidemiology, University of California Irvine, Irvine, CA, USA.
78
Women's Cancer, Institute for Women's Health, University College London, London, UK.
79
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
80
Department of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
81
Department of Gynecologic Oncology, The Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Abstract

BACKGROUND:

Observational studies have reported a positive association between body mass index (BMI) and ovarian cancer risk. However, questions remain as to whether this represents a causal effect, or holds for all histological subtypes. The lack of association observed for serous cancers may, for instance, be due to disease-associated weight loss. Mendelian randomization (MR) uses genetic markers as proxies for risk factors to overcome limitations of observational studies. We used MR to elucidate the relationship between BMI and ovarian cancer, hypothesizing that genetically predicted BMI would be associated with increased risk of non-high grade serous ovarian cancers (non-HGSC) but not HGSC.

METHODS:

We pooled data from 39 studies (14 047 cases, 23 003 controls) in the Ovarian Cancer Association Consortium. We constructed a weighted genetic risk score (GRS, partial F-statistic = 172), summing alleles at 87 single nucleotide polymorphisms previously associated with BMI, weighting by their published strength of association with BMI. Applying two-stage predictor-substitution MR, we used logistic regression to estimate study-specific odds ratios (OR) and 95% confidence intervals (CI) for the association between genetically predicted BMI and risk, and pooled these using random-effects meta-analysis.

RESULTS:

Higher genetically predicted BMI was associated with increased risk of non-HGSC (pooled OR = 1.29, 95% CI 1.03-1.61 per 5 units BMI) but not HGSC (pooled OR = 1.06, 95% CI 0.88-1.27). Secondary analyses stratified by behaviour/subtype suggested that, consistent with observational data, the association was strongest for low-grade/borderline serous cancers (OR = 1.93, 95% CI 1.33-2.81).

CONCLUSIONS:

Our data suggest that higher BMI increases risk of non-HGSC, but not the more common and aggressive HGSC subtype, confirming the observational evidence.

KEYWORDS:

Body mass index; Mendelian randomization analysis; obesity; ovarian neoplasms

PMID:
27401727
PMCID:
PMC5644573
DOI:
10.1093/ije/dyw158
[Indexed for MEDLINE]
Free PMC Article

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