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

Francesmary Modugno; Zhuxuan Fu; Susan J Jordan; Aocs Group; Jenny Chang-Claude; Renée T Fortner; Marc T Goodman; Kirsten B Moysich; Joellen M Schildkraut; Andrew Berchuck; Elisa V Bandera; Bo Qin; Rebecca Sutphen; John R McLaughlin; Usha Menon; Susan J Ramus; Simon A Gayther; Aleksandra Gentry-Maharaj; Chloe Karpinskyj; Celeste L Pearce; Anna H Wu; Harvey A Risch; Penelope M Webb

doi:10.1007/s10654-020-00682-9

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

Eur J Epidemiol. 2020 Nov;35(11):1025-1042. doi: 10.1007/s10654-020-00682-9. Epub 2020 Sep 21.

Authors

Francesmary Modugno^{1

2}, Zhuxuan Fu³, Susan J Jordan^{4

5}, Aocs Group^{5

6

7}, Jenny Chang-Claude^{8

9}, Renée T Fortner⁸, Marc T Goodman¹⁰, Kirsten B Moysich¹¹, Joellen M Schildkraut¹², Andrew Berchuck¹³, Elisa V Bandera¹⁴, Bo Qin¹⁴, Rebecca Sutphen¹⁵, John R McLaughlin¹⁶, Usha Menon¹⁷, Susan J Ramus^{18

19}, Simon A Gayther²⁰, Aleksandra Gentry-Maharaj¹⁷, Chloe Karpinskyj¹⁷, Celeste L Pearce^{21

22}, Anna H Wu²³, Harvey A Risch²⁴, Penelope M Webb⁵

Affiliations

¹ Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, 15213, USA. [email protected].
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. [email protected].
³ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, 15213, USA.
⁴ School of Public Health, University of Queensland, Herston, QLD, Australia.
⁵ Population Health Department, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
⁶ Peter MacCallum Cancer Center, Melbourne, VIC, 3000, Australia.
⁷ Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, 2145, Australia.
⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
⁹ Cancer Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁰ Cancer Prevention and Genetics Program, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
¹¹ Division of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
¹² Department of Public Health Sciences, University of Virginia, Box 800717, Charlottesville, VA, 22908, USA.
¹³ Department of Gynecologic Oncology, Duke University Medical Center, DUMC 3079, Durham, NC, 27710, USA.
¹⁴ Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA.
¹⁵ Epidemiology Center, College of Medicine, University of South Florida, Tampa, FL, 33612, USA.
¹⁶ Public Health Ontario, Samuel Lunenfeld Research Institute, Toronto, ON, M5T3L9, Canada.
¹⁷ MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, WC1V 6LJ, UK.
¹⁸ Faculty of Medicine, School of Women's and Children's Health, University of NSW Sydney, Sydney, NSW, 2052, Australia.
¹⁹ Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, NSW, 2052, Australia.
²⁰ Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
²¹ Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
²² Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, 90033, USA.
²³ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
²⁴ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06510, USA.

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.

Keywords: Case–control study; Endometrioid ovarian cancer; Epithelial ovarian cancer; Mucinous ovarian cancer; Offspring sex; Pooled analysis.

MeSH terms

Adult
Carcinoma, Ovarian Epithelial / etiology*
Carcinoma, Ovarian Epithelial / pathology
Endometriosis / etiology*
Endometriosis / pathology
Female
Gender Identity
Humans
Infant, Newborn
Male
Middle Aged
Ovarian Neoplasms / etiology*
Ovarian Neoplasms / pathology
Pregnancy

Abstract

MeSH terms

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