Lifetime ovulatory years and ovarian cancer gene expression profiles

Naoko Sasamoto; Paul A Stewart; Tianyi Wang; Sean J Yoder; Srikumar Chellappan; Jonathan L Hecht; Brooke L Fridley; Kathryn L Terry; Shelley S Tworoger

doi:10.1186/s13048-022-00995-1

Lifetime ovulatory years and ovarian cancer gene expression profiles

J Ovarian Res. 2022 May 13;15(1):59. doi: 10.1186/s13048-022-00995-1.

Authors

Naoko Sasamoto¹, Paul A Stewart², Tianyi Wang³, Sean J Yoder⁴, Srikumar Chellappan⁵, Jonathan L Hecht⁶, Brooke L Fridley², Kathryn L Terry^{7

8}, Shelley S Tworoger³

Affiliations

¹ Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA. nsasamoto@bwh.harvard.edu.
² Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
³ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁴ Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁵ Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
⁶ Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
⁷ Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, 221 Longwood Avenue, Boston, MA, 02115, USA.
⁸ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Abstract

Background: Greater ovulatory years is associated with increased ovarian cancer risk. Although ovulation leads to an acute pro-inflammatory local environment, how long-term exposure to ovulation impacts ovarian carcinogenesis is not fully understood. Thus, we examined the association between gene expression profiles of ovarian tumors and lifetime ovulatory years to enhance understanding of associated biological pathways.

Methods: RNA sequencing data was generated on 234 invasive ovarian cancer tumors that were high-grade serous, poorly differentiated, or high-grade endometrioid from the Nurses' Health Study (NHS), NHSII, and the New England Case Control Study. We used linear regression to identify differentially expressed genes by estimated ovulatory years, adjusted for birth decade and cohort, overall and stratified by menopausal status at diagnosis. We used false discovery rates (FDR) to account for multiple testing. Gene set enrichment analysis (GSEA) with Cancer Hallmarks, KEGG, and Reactome databases was used to identify biological pathways associated with ovulatory years.

Results: No individual genes were significantly differentially expressed by ovulatory years (FDR > 0.19). However, GSEA identified several pathways that were significantly associated with ovulatory years, including downregulation of pathways related to inflammation and proliferation (FDR < 1.0 × 10^-5). Greater ovulatory years were more strongly associated with downregulation of genes related to proliferation (e.g., E2F targets, FDR = 1.53 × 10^-24; G2M checkpoints, FDR = 3.50 × 10^-22) among premenopausal versus postmenopausal women at diagnosis. The association of greater ovulatory years with downregulation of genes involved in inflammatory response such as interferon gamma response pathways (FDR = 7.81 × 10^-17) was stronger in postmenopausal women.

Conclusions: Our results provide novel insight into the biological pathways that link ovulatory years to ovarian carcinogenesis, which may lead to development of targeted prevention strategies for ovarian cancer.

Keywords: Carcinogenesis; Gene expression; Ovarian cancer tumor; Ovulatory years; RNA sequencing.

MeSH terms

Carcinogenesis
Carcinoma, Ovarian Epithelial
Case-Control Studies
Female
Humans
Ovarian Neoplasms* / genetics
Ovarian Neoplasms* / pathology
Transcriptome*

Abstract

MeSH terms

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