Suzanne C Dixon1, Christina M Nagle2, Aaron P Thrift3, Paul Dp Pharoah4, Celeste Leigh Pearce5, Wei Zheng6, Jodie N Painter7, 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. 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.
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.
Authors: Christina M Nagle; Catherine M Olsen; Penelope M Webb; Susan J Jordan; David C Whiteman; Adèle C Green Journal: Eur J Cancer Date: 2008-08-15 Impact factor: 9.162
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