Holly R Harris1,2, Kara L Cushing-Haugen1, Penelope M Webb3,4, Christina M Nagle3,4, Susan J Jordan3,4, Harvey A Risch5, Mary Anne Rossing1,2, Jennifer A Doherty6, Marc T Goodman7,8, Francesmary Modugno9, Roberta B Ness10, Kirsten B Moysich11, Susanne K Kjær12,13, Estrid Høgdall12,14, Allan Jensen12, Joellen M Schildkraut15, Andrew Berchuck16, Daniel W Cramer17,18, Elisa V Bandera19, Lorna Rodriguez19, Nicolas Wentzensen20, Joanne Kotsopoulos21, Steven A Narod21, John R McLaughlin22, Hoda Anton-Culver23, Argyrios Ziogas23, Celeste L Pearce24,25, Anna H Wu25, Sara Lindström1,2, Kathryn L Terry17,18. 1. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 2. Department of Epidemiology, University of Washington, Seattle, WA, USA. 3. Population Health Department, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. 4. School of Public Health, University of Queensland, Herston, Queensland, Australia. 5. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA. 6. Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA. 7. Caner Prevention and Genetics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 8. Department of Biomedical Sciences, Community and Population Health Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. 9. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. 10. The University of Texas School of Public Health, Houston, TX, USA. 11. Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA. 12. Department of Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark. 13. Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark. 14. Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark. 15. Department of Public Health Sciences, The University of Virginia, Charlottesville, VA, USA. 16. Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA. 17. Obstetrics and Gynecology Epidemiology Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. 18. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 19. Division of Obstetrics and Gynecology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ, USA. 20. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 21. Epidemiology Division, Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada. 22. Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, Canada. 23. Department of Medicine, University of California Irvine, Irvine, CA, USA. 24. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, USA. 25. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA.
Abstract
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder with an estimated prevalence of 4-21% in reproductive aged women. Recently, the Ovarian Cancer Association Consortium (OCAC) reported a decreased risk of invasive ovarian cancer among women with self-reported PCOS. However, given the limitations of self-reported PCOS, the validity of these observed associations remains uncertain. Therefore, we sought to use Mendelian randomization with genetic markers as a proxy for PCOS, to examine the association between PCOS and ovarian cancer. METHODS: Utilizing 14 single nucleotide polymorphisms (SNPs) previously associated with PCOS we assessed the association between genetically predicted PCOS and ovarian cancer risk, overall and by histotype, using summary statistics from a previously conducted genome-wide association study (GWAS) of ovarian cancer among European ancestry women within the OCAC (22 406 with invasive disease, 3103 with borderline disease and 40 941 controls). RESULTS: An inverse association was observed between genetically predicted PCOS and invasive ovarian cancer risk: odds ratio (OR)=0.92 [95% confidence interval (CI)=0.85-0.99; P = 0.03]. When results were examined by histotype, the strongest inverse association was observed between genetically predicted PCOS and endometrioid tumors (OR = 0.77; 95% CI = 0.65-0.92; P = 0.003). Adjustment for individual-level body mass index, oral contraceptive use and parity did not materially change the associations. CONCLUSION: Our study provides evidence for a relationship between PCOS and reduced ovarian cancer risk, overall and among specific histotypes of invasive ovarian cancer. These results lend support to our previous observational study results. Future studies are needed to understand mechanisms underlying this association.
Authors: Ricardo Azziz; Enrico Carmina; Didier Dewailly; Evanthia Diamanti-Kandarakis; Hector F Escobar-Morreale; Walter Futterweit; Onno E Janssen; Richard S Legro; Robert J Norman; Ann E Taylor; Selma F Witchel Journal: J Clin Endocrinol Metab Date: 2006-08-29 Impact factor: 5.958
Authors: Catherine M Olsen; Christina M Nagle; David C Whiteman; Roberta Ness; Celeste Leigh Pearce; Malcolm C Pike; Mary Anne Rossing; Kathryn L Terry; Anna H Wu; Harvey A Risch; Herbert Yu; Jennifer A Doherty; Jenny Chang-Claude; Rebecca Hein; Stefan Nickels; Shan Wang-Gohrke; Marc T Goodman; Michael E Carney; Rayna K Matsuno; Galina Lurie; Kirsten Moysich; Susanne K Kjaer; Allan Jensen; Estrid Hogdall; Ellen L Goode; Brooke L Fridley; Robert A Vierkant; Melissa C Larson; Joellen Schildkraut; Cathrine Hoyo; Patricia Moorman; Rachel P Weber; Daniel W Cramer; Allison F Vitonis; Elisa V Bandera; Sara H Olson; Lorna Rodriguez-Rodriguez; Melony King; Louise A Brinton; Hannah Yang; Montserrat Garcia-Closas; Jolanta Lissowska; Hoda Anton-Culver; Argyrios Ziogas; Simon A Gayther; Susan J Ramus; Usha Menon; Aleksandra Gentry-Maharaj; Penelope M Webb Journal: Endocr Relat Cancer Date: 2013-03-22 Impact factor: 5.678
Authors: Catherine M Olsen; Adèle C Green; Christina M Nagle; Susan J Jordan; David C Whiteman; Christopher J Bain; Penelope M Webb Journal: Endocr Relat Cancer Date: 2008-09-04 Impact factor: 5.678
Authors: Suzanne C Dixon; Christina M Nagle; Aaron P Thrift; Paul Dp Pharoah; Celeste Leigh Pearce; Wei Zheng; Jodie N Painter; 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 Journal: Int J Epidemiol Date: 2016-07-10 Impact factor: 7.196