Dataset Information

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

ABSTRACT:

Background

The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

Methods

LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with expected estimates assuming 1 year of ovulation suppression has the same effect regardless of source.

Results

LOY was associated with increased EOC risk (OR per year increase = 1.014, 95% CI = 1.009 to 1.020 to OR per year increase = 1.044, 95% CI = 1.041 to 1.048). Individual LOY components, except age at menarche, also associated with EOC. The estimated model coefficient for oral contraceptive use and pregnancies were 4.45 times and 12- to 15-fold greater than expected, respectively. LOY was associated with high-grade serous, low-grade serous, endometrioid, and clear cell histotypes (ORs per year increase = 1.054, 1.040, 1.065, and 1.098, respectively) but not mucinous tumors. Estimated coefficients of LOY components were close to expected estimates for high-grade serous but larger than expected for low-grade serous, endometrioid, and clear cell histotypes.

Conclusions

LOY is positively associated with nonmucinous EOC. Differences between estimated and expected model coefficients for LOY components suggest factors beyond ovulation underlie the associations between LOY components and EOC in general and for non-HGSOC.

SUBMITTER: Fu Z

PROVIDER: S-EPMC10165492 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Publications

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

Fu Zhuxuan Z Brooks Maria Mori MM Irvin Sarah S Jordan Susan S Aben Katja K H KKH Anton-Culver Hoda H Bandera Elisa V EV Beckmann Matthias W MW Berchuck Andrew A Brooks-Wilson Angela A Chang-Claude Jenny J Cook Linda S LS Cramer Daniel W DW Cushing-Haugen Kara L KL Doherty Jennifer A JA Ekici Arif B AB Fasching Peter A PA Fortner Renée T RT Gayther Simon A SA Gentry-Maharaj Aleksandra A Giles Graham G GG Goode Ellen L EL Goodman Marc T MT Harris Holly R HR Hein Alexander A Kaaks Rudolf R Kiemeney Lambertus A LA Köbel Martin M Kotsopoulos Joanne J Le Nhu D ND Lee Alice W AW Matsuo Keitaro K McGuire Valerie V McLaughlin John R JR Menon Usha U Milne Roger L RL Moysich Kirsten B KB Pearce Celeste Leigh CL Pike Malcolm C MC Qin Bo B Ramus Susan J SJ Riggan Marjorie J MJ Rothstein Joseph H JH Schildkraut Joellen M JM Sieh Weiva W Sutphen Rebecca R Terry Kathryn L KL Thompson Pamela J PJ Titus Linda L van Altena Anne M AM White Emily E Whittemore Alice S AS Wu Anna H AH Zheng Wei W Ziogas Argyrios A Taylor Sarah E SE Tang Lu L Songer Thomas T Wentzensen Nicolas N Webb Penelope M PM Risch Harvey A HA Modugno Francesmary F

Journal of the National Cancer Institute 20230501 5

<h4>Background</h4>The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.<h4>Methods</h4>LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 co ...[more]

PMID: 36688720

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Project description:BackgroundGreater 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.MethodsRNA 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.ResultsNo 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.ConclusionsOur 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.

Project description:Repeated exposure to the acute proinflammatory environment that follows ovulation at the ovarian surface and distal fallopian tube over a woman's reproductive years may increase ovarian cancer risk. To address this, analyses included individual-level data from 558,709 naturally menopausal women across 20 prospective cohorts, among whom 3,246 developed invasive epithelial ovarian cancer (2,045 serous, 319 endometrioid, 184 mucinous, 121 clear cell, 577 other/unknown). Cox models were used to estimate multivariable-adjusted HRs between lifetime ovulatory cycles (LOC) and its components and ovarian cancer risk overall and by histotype. Women in the 90th percentile of LOC (>514 cycles) were almost twice as likely to be diagnosed with ovarian cancer than women in the 10th percentile (<294) [HR (95% confidence interval): 1.92 (1.60-2.30)]. Risk increased 14% per 5-year increase in LOC (60 cycles) [(1.10-1.17)]; this association remained after adjustment for LOC components: number of pregnancies and oral contraceptive use [1.08 (1.04-1.12)]. The association varied by histotype, with increased risk of serous [1.13 (1.09-1.17)], endometrioid [1.20 (1.10-1.32)], and clear cell [1.37 (1.18-1.58)], but not mucinous [0.99 (0.88-1.10), P-heterogeneity = 0.01] tumors. Heterogeneity across histotypes was reduced [P-heterogeneity = 0.15] with adjustment for LOC components [1.08 serous, 1.11 endometrioid, 1.26 clear cell, 0.94 mucinous]. Although the 10-year absolute risk of ovarian cancer is small, it roughly doubles as the number of LOC rises from approximately 300 to 500. The consistency and linearity of effects strongly support the hypothesis that each ovulation leads to small increases in the risk of most ovarian cancers, a risk that cumulates through life, suggesting this as an important area for identifying intervention strategies. SIGNIFICANCE: Although ovarian cancer is rare, risk of most ovarian cancers doubles as the number of lifetime ovulatory cycles increases from approximately 300 to 500. Thus, identifying an important area for cancer prevention research.

Dataset Information

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

Background

Methods

Results

Conclusions

Publications

Lifetime ovulatory years and risk of epithelial ovarian cancer: a multinational pooled analysis.

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