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

Suzanne C Dixon; Christina M Nagle; Aaron P Thrift; Paul Dp Pharoah; Celeste Leigh Pearce; Wei Zheng; Jodie N Painter; AOCS Group & Australian Cancer Study (Ovarian Cancer); Georgia Chenevix-Trench; Peter A Fasching; Matthias W Beckmann; Diether Lambrechts; Ignace Vergote; Sandrina Lambrechts; Els Van Nieuwenhuysen; Mary Anne Rossing; Jennifer A Doherty; Kristine G Wicklund; Jenny Chang-Claude; Anja Rudolph; Kirsten B Moysich; Kunle Odunsi; Marc T Goodman; Lynne R Wilkens; Pamela J Thompson; Yurii B Shvetsov; Thilo Dörk; Tjoung-Won Park-Simon; Peter Hillemanns; Natalia Bogdanova; Ralf Butzow; Heli Nevanlinna; Liisa M Pelttari; Arto Leminen; Francesmary Modugno; Roberta B Ness; Robert P Edwards; Joseph L Kelley; Florian Heitz; Beth Y Karlan; Susanne K Kjær; Estrid Høgdall; Allan Jensen; Ellen L Goode; Brooke L Fridley; Julie M Cunningham; Stacey J Winham; Graham G Giles; Fiona Bruinsma; Roger L Milne; Melissa C Southey; Michelle A T Hildebrandt; Xifeng Wu; Karen H Lu; Dong Liang; Douglas A Levine; Maria Bisogna; Joellen M Schildkraut; Andrew Berchuck; Daniel W Cramer; Kathryn L Terry; Elisa V Bandera; Sara H Olson; Helga B Salvesen; Liv Cecilie Thomsen; Reidun K Kopperud; Line Bjorge; Lambertus A Kiemeney; Leon F A G Massuger; Tanja Pejovic; Linda S Cook; Nhu D Le; Kenneth D Swenerton; Angela Brooks-Wilson; Linda E Kelemen; Jan Lubiński; Tomasz Huzarski; Jacek Gronwald; Janusz Menkiszak; Nicolas Wentzensen; Louise Brinton; Hannah Yang; Jolanta Lissowska; Claus K Høgdall; Lene Lundvall; Honglin Song; Jonathan P Tyrer; Ian Campbell; Diana Eccles; James Paul; Rosalind Glasspool; Nadeem Siddiqui; Alice S Whittemore; Weiva Sieh; Valerie McGuire; Joseph H Rothstein; Steven A Narod; Catherine Phelan; Harvey A Risch; John R McLaughlin; Hoda Anton-Culver; Argyrios Ziogas; Usha Menon; Simon A Gayther; Susan J Ramus; Aleksandra Gentry-Maharaj; Anna H Wu; Malcolm C Pike; Chiu-Chen Tseng; Jolanta Kupryjanczyk; Agnieszka Dansonka-Mieszkowska; Agnieszka Budzilowska; Beata Spiewankiewicz; Penelope M Webb; Ovarian Cancer Association Consortium

doi:10.1093/ije/dyw158

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

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

Authors

Suzanne C Dixon¹, Christina M Nagle², Aaron P Thrift³, Paul Dp Pharoah⁴, Celeste Leigh Pearce⁵, Wei Zheng⁶, Jodie N Painter⁷; AOCS Group & Australian Cancer Study (Ovarian Cancer); Georgia Chenevix-Trench⁸, Peter A Fasching⁹, Matthias W Beckmann¹⁰, Diether Lambrechts¹¹, Ignace Vergote¹², Sandrina Lambrechts¹², Els Van Nieuwenhuysen¹², Mary Anne Rossing¹³, Jennifer A Doherty¹⁴, Kristine G Wicklund¹⁵, Jenny Chang-Claude¹⁶, Anja Rudolph¹⁶, Kirsten B Moysich¹⁷, Kunle Odunsi¹⁸, Marc T Goodman¹⁹, Lynne R Wilkens²⁰, Pamela J Thompson²¹, Yurii B Shvetsov²⁰, Thilo Dörk²², Tjoung-Won Park-Simon²², Peter Hillemanns²², Natalia Bogdanova²³, Ralf Butzow²⁴, Heli Nevanlinna²⁵, Liisa M Pelttari²⁵, Arto Leminen²⁵, Francesmary Modugno²⁶, Roberta B Ness²⁷, Robert P Edwards²⁸, Joseph L Kelley²⁹, Florian Heitz³⁰, Beth Y Karlan³¹, Susanne K Kjær³², Estrid Høgdall³³, Allan Jensen³⁴, Ellen L Goode³⁵, Brooke L Fridley³⁶, Julie M Cunningham³⁷, Stacey J Winham³⁸, Graham G Giles³⁹, Fiona Bruinsma⁴⁰, Roger L Milne⁴¹, Melissa C Southey⁴², Michelle A T Hildebrandt⁴³, Xifeng Wu⁴³, Karen H Lu⁴⁴, Dong Liang⁴⁵, Douglas A Levine⁴⁶, Maria Bisogna⁴⁶, Joellen M Schildkraut⁴⁷, Andrew Berchuck⁴⁸, Daniel W Cramer⁴⁹, Kathryn L Terry⁴⁹, Elisa V Bandera⁵⁰, Sara H Olson⁵¹, Helga B Salvesen⁵², Liv Cecilie Thomsen⁵², Reidun K Kopperud⁵², Line Bjorge⁵², Lambertus A Kiemeney⁵³, Leon F A G Massuger⁵⁴, Tanja Pejovic⁵⁵, Linda S Cook⁵⁶, Nhu D Le⁵⁷, Kenneth D Swenerton⁵⁸, Angela Brooks-Wilson⁵⁹, Linda E Kelemen⁶⁰, Jan Lubiński⁶¹, Tomasz Huzarski⁶¹, Jacek Gronwald⁶¹, Janusz Menkiszak⁶², Nicolas Wentzensen⁶³, Louise Brinton⁶³, Hannah Yang⁶³, Jolanta Lissowska⁶⁴, Claus K Høgdall⁶⁵, Lene Lundvall⁶⁵, Honglin Song⁶⁶, Jonathan P Tyrer⁶⁶, Ian Campbell⁶⁷, Diana Eccles⁶⁸, James Paul⁶⁹, Rosalind Glasspool⁶⁹, Nadeem Siddiqui⁷⁰, Alice S Whittemore⁷¹, Weiva Sieh⁷¹, Valerie McGuire⁷¹, Joseph H Rothstein⁷¹, Steven A Narod⁷², Catherine Phelan⁷³, Harvey A Risch⁷⁴, John R McLaughlin⁷⁵, Hoda Anton-Culver⁷⁶, Argyrios Ziogas⁷⁷, Usha Menon⁷⁸, Simon A Gayther⁷⁹, Susan J Ramus⁷⁹, Aleksandra Gentry-Maharaj⁷⁸, Anna H Wu⁷⁹, Malcolm C Pike⁵¹, Chiu-Chen Tseng⁷⁹, Jolanta Kupryjanczyk⁸⁰, Agnieszka Dansonka-Mieszkowska⁸⁰, Agnieszka Budzilowska⁸⁰, Beata Spiewankiewicz⁸¹, Penelope M Webb²; Ovarian Cancer Association Consortium

Affiliations

¹ Gynaecological Cancers Group, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia The University of Queensland, School of Public Health, Brisbane, QLD, Australia [email protected].
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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Body Mass Index*
Female
Genetic Markers
Genome-Wide Association Study
Genotype
Humans
Logistic Models
Mendelian Randomization Analysis
Meta-Analysis as Topic
Middle Aged
Multivariate Analysis
Obesity / complications
Obesity / genetics*
Ovarian Neoplasms / epidemiology
Ovarian Neoplasms / genetics*
Polymorphism, Single Nucleotide*
Risk Factors
Young Adult

Substances

Genetic Markers

Abstract

Publication types

MeSH terms

Substances

Grants and funding