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Offspring sex and risk of epithelial ovarian cancer: a multinational pooled analysis of 12 case–control studies

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Abstract

While childbearing protects against risk of epithelial ovarian cancer (EOC), few studies have explored the impact on maternal EOC risk of sex of offspring, which may affect the maternal environment during pregnancy. We performed a pooled analysis among parous participants from 12 case–controls studies comprising 6872 EOC patients and 9101 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression for case–control associations and polytomous logistic regression for histotype-specific associations, all adjusted for potential confounders. In general, no associations were found between offspring sex and EOC risk. However, compared to bearing only female offspring, bearing one or more male offspring was associated with increased risk of mucinous EOC (OR = 1.45; 95% CI = 1.01-2.07), which appeared to be limited to women reporting menarche before age 13 compared to later menarche (OR = 1.71 vs 0.99; P-interaction = 0.02). Bearing increasing numbers of male offspring was associated with greater risks of mucinous tumors (OR = 1.31, 1.84, 2.31, for 1, 2 and 3 or more male offspring, respectively; trend-p = 0.005). Stratifying by hormonally-associated conditions suggested that compared to bearing all female offspring, bearing a male offspring was associated with lower risk of endometrioid cancer among women with a history of adult acne, hirsutism, or polycystic ovary syndrome (OR = 0.49, 95% CI = 0.28-0.83) but with higher risk among women without any of those conditions (OR = 1.64 95% CI = 1.14–2.34; P-interaction = 0.003). Offspring sex influences the childbearing-EOC risk relationship for specific histotypes and conditions. These findings support the differing etiologic origins of EOC histotypes and highlight the importance of EOC histotype-specific epidemiologic studies. These findings also suggest the need to better understand how pregnancy affects EOC risk

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Acknowledgements

We are grateful to the family and friends of Kathryn Sladek Smith for their generous support of the Ovarian Cancer Association Consortium through their donations to the Ovarian Cancer Research Fund. We thank the study participants, doctors, nurses, research staff, clinical and scientific collaborators, health care providers, and health information sources who have contributed to the many studies contributing to this manuscript. Acknowledgements for individual studies: AUS: The AOCS also acknowledges the cooperation of the participating institutions in Australia, and the contribution of the study nurses, research assistants and all clinical and scientific collaborators. The complete AOCS Study Group can be found at www.aocstudy.org. We would like to thank all of the women who participated in this research program; CON: The cooperation of the 32 Connecticut hospitals, including Stamford Hospital, in allowing patient access, is gratefully acknowledged. This study was approved by the State of Connecticut Department of Public Health Human Investigation Committee. Certain data used in this study were obtained from the Connecticut Tumor Registry in the Connecticut Department of Public Health. The authors assume full responsibility for analyses and interpretation of these data; GER: The German Ovarian Cancer Study (GER) thank Sabine Behrens for competent technical assistance; UKO: We particularly thank I. Jacobs, M. Widschwendter, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study.

Funding

The Ovarian Cancer Association Consortium was supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Funding for individual studies: AUS: The Australian Ovarian Cancer Study (AOCS) was supported by the U.S. Army Medical Research and Materiel Command (DAMD17-01-1-0729), National Health & Medical Research Council of Australia (199600, 400413 and 400281), Cancer Councils of New South Wales, Victoria, Queensland, South Australia and Tasmania and Cancer Foundation of Western Australia (Multi-State Applications 191, 211 and 182). AOCS gratefully acknowledges additional support from Ovarian Cancer Australia and the Peter MacCallum Foundation; CON: National Institutes of Health (R01-CA074850; R01-CA080742); DKE: Ovarian Cancer Research Fund; GER: German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research (01 GB 9401) and the German Cancer Research Center (DKFZ); HAW: U.S. National Institutes of Health (R01-CA58598, N01-CN-55424 and N01-PC-67001); HOP: University of Pittsburgh School of Medicine Dean’s Faculty Advancement Award (F. Modugno), Department of Defense (DAMD17-02-1-0669) and NCI (K07-CA080668, R01-CA95023, MO1-RR000056 R01-CA126841); NCO: National Institutes of Health (R01-CA76016) and the Department of Defense (DAMD17-02-1-0666); NJO: National Cancer Institute (NIH-K07 CA095666, R01-CA83918, NIH-K22-CA138563, and P30-CA072720) and Rutgers Cancer Institute of New Jersey; SON: National Health Research and Development Program, Health Canada, grant 6613-1415-53; TBO: National Institutes of Health (R01-CA106414-A2), American Cancer Society (CRTG-00-196-01-CCE), Department of Defense (DAMD17-98-1-8659), Celma Mastery Ovarian Cancer Foundation; TOR: NIH grants R01 CA063678 and R01 CA063682; UKO: The UKOPS study was funded by The Eve Appeal (The Oak Foundation) with investigators supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and MRC core funding (MR_UU_12023); USC: P01CA17054, P30CA14089, R01CA61132, N01PC67010, R03CA113148, R03CA115195, N01CN025403, and California Cancer Research Program (00-01389 V-20170, 2II0200).

Author information

Authors and Affiliations

  1. Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, 15213, USA

    Francesmary Modugno

  2. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Magee-Womens Hospital of UPMC, Suite 2130, 300 Halket Street, Pittsburgh, PA, 15213, USA

    Francesmary Modugno

  3. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15213, USA

    Zhuxuan Fu

  4. School of Public Health, University of Queensland, Herston, QLD, Australia

    Susan J. Jordan

  5. Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia

    Susan J. Jordan, AOCS Group & Penelope M. Webb

  6. Peter MacCallum Cancer Center, Melbourne, VIC, 3000, Australia

    AOCS Group

  7. Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, 2145, Australia

    AOCS Group

  8. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany

    Jenny Chang-Claude & Renée T. Fortner

  9. Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Jenny Chang-Claude

  10. Cancer Prevention and Genetics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Marc T. Goodman

  11. Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Kirsten B. Moysich

  12. Department of Public Health Sciences, University of Virginia, Box 800717, Charlottesville, VA, 22908, USA

    Joellen M. Schildkraut

  13. Department of Gynecologic Oncology, Duke University Medical Center, DUMC 3079, Durham, NC, 27710, USA

    Andrew Berchuck

  14. Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Elisa V. Bandera & Bo Qin

  15. Epidemiology Center, College of Medicine, University of South Florida, Tampa, FL, 33612, USA

    Rebecca Sutphen

  16. Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, ON, M5T3L9, Canada

    John R. McLaughlin

  17. MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK

    Usha Menon, Aleksandra Gentry-Maharaj & Chloe Karpinskyj

  18. Faculty of Medicine, School of Women’s and Children’s Health, University of NSW Sydney, Sydney, NSW, 2052, Australia

    Susan J. Ramus

  19. Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, 2052, Australia

    Susan J. Ramus

  20. Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

    Simon A. Gayther

  21. Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA

    Celeste L. Pearce

  22. Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA

    Celeste L. Pearce

  23. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA

    Anna H. Wu

  24. Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06510, USA

    Harvey A. Risch

Authors
  1. Francesmary Modugno
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  2. Zhuxuan Fu
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  3. Susan J. Jordan
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  4. AOCS Group
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  13. Rebecca Sutphen
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  14. John R. McLaughlin
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  15. Usha Menon
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  16. Susan J. Ramus
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  17. Simon A. Gayther
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  18. Aleksandra Gentry-Maharaj
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  19. Chloe Karpinskyj
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  20. Celeste L. Pearce
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  21. Anna H. Wu
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  22. Harvey A. Risch
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  23. Penelope M. Webb
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Corresponding author

Correspondence to Francesmary Modugno.

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Usha Menon has stock ownership awarded to her by UCL in Abcodia. No other authors report conflicts of interest.

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Modugno, F., Fu, Z., Jordan, S.J. et al. Offspring sex and risk of epithelial ovarian cancer: a multinational pooled analysis of 12 case–control studies. Eur J Epidemiol 35, 1025–1042 (2020). https://doi.org/10.1007/s10654-020-00682-9

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  • DOI: https://doi.org/10.1007/s10654-020-00682-9

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