Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

doi:10.1093/ije/dyz113

. 2019 Jun 1;48(3):822-830.

doi: 10.1093/ije/dyz113.

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

Holly R Harris^{1

2}, Kara L Cushing-Haugen¹, Penelope M Webb^{3

4}, Christina M Nagle^{3

4}, Susan J Jordan^{3

4}; Australian Ovarian Cancer Study Group; Harvey A Risch⁵, Mary Anne Rossing^{1

2}, Jennifer A Doherty⁶, Marc T Goodman^{7

8}, Francesmary Modugno⁹, Roberta B Ness¹⁰, Kirsten B Moysich¹¹, Susanne K Kjær^{12

13}, Estrid Høgdall^{12

14}, Allan Jensen¹², Joellen M Schildkraut¹⁵, Andrew Berchuck¹⁶, Daniel W Cramer^{17

18}, Elisa V Bandera¹⁹, Lorna Rodriguez¹⁹, Nicolas Wentzensen²⁰, Joanne Kotsopoulos²¹, Steven A Narod²¹, John R McLaughlin²², Hoda Anton-Culver²³, Argyrios Ziogas²³, Celeste L Pearce^{24

25}, Anna H Wu²⁵, Sara Lindström^{1

2}, Kathryn L Terry^{17

18}

Affiliations

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.

PMID: 31211375
PMCID: PMC6659359
DOI: 10.1093/ije/dyz113

Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

Holly R Harris et al. Int J Epidemiol. 2019.

. 2019 Jun 1;48(3):822-830.

doi: 10.1093/ije/dyz113.

Authors

Affiliations

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.

PMID: 31211375
PMCID: PMC6659359
DOI: 10.1093/ije/dyz113

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.

Keywords: Mendelian randomization; Polycystic ovary syndrome; histotype; ovarian cancer.

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Comment in

Commentary: Mendelian randomization and women's health.
Censin JC, Bovijn J, Holmes MV, Lindgren CM. Censin JC, et al. Int J Epidemiol. 2019 Jun 1;48(3):830-833. doi: 10.1093/ije/dyz141. Int J Epidemiol. 2019. PMID: 31292646 Free PMC article. No abstract available.

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References

1. March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ.. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25:544–51. - PubMed
1. National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome: Executive Summary. In: Health NIo, editor; 2012. Available at: https://prevention.nih.gov/sites/default/files/2018-06/FinalReport.pdf.
1. Barry JA, Azizia MM, Hardiman PJ.. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2014;20:748–58. - PMC - PubMed
1. Harris H, Polycystic TK.. ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract 2016;2:1–9. - PMC - PubMed
1. Harris HR, Babic A, Webb PM, et al. Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev2017;27:174–82. - PMC - PubMed

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[1] March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ.. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25:544–51. - PubMed

[2] March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ.. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod 2010;25:544–51. - PubMed

[3] National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome: Executive Summary. In: Health NIo, editor; 2012. Available at: https://prevention.nih.gov/sites/default/files/2018-06/FinalReport.pdf.

[4] National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome: Executive Summary. In: Health NIo, editor; 2012. Available at: https://prevention.nih.gov/sites/default/files/2018-06/FinalReport.pdf.

[5] Barry JA, Azizia MM, Hardiman PJ.. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2014;20:748–58. - PMC - PubMed

[6] Barry JA, Azizia MM, Hardiman PJ.. Risk of endometrial, ovarian and breast cancer in women with polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update 2014;20:748–58. - PMC - PubMed

[7] Harris H, Polycystic TK.. ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract 2016;2:1–9. - PMC - PubMed

[8] Harris H, Polycystic TK.. ovary syndrome and risk of endometrial, ovarian, and breast cancer: a systematic review. Fertil Res Pract 2016;2:1–9. - PMC - PubMed

[9] Harris HR, Babic A, Webb PM, et al. Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev2017;27:174–82. - PMC - PubMed

[10] Harris HR, Babic A, Webb PM, et al. Polycystic ovary syndrome, oligomenorrhea, and risk of ovarian cancer histotypes: evidence from the Ovarian Cancer Association Consortium. Cancer Epidemiol Biomarkers Prev2017;27:174–82. - PMC - PubMed

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Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

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Association between genetically predicted polycystic ovary syndrome and ovarian cancer: a Mendelian randomization study

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