Study On Risk Factors Of Ovarian Cancer Based On Gonadotropin

Background:Ovarian cancer is one of the most common gynecologic malignancies,the most common type being epithelial.The five-year survival rate of ovarian cancer patients diagnosed at early stage is 92%,while it is less than 30%for patients diagnosed at late stage.However,most of ovarian cancer patients are diagnosed at late stage because patients have no obvious symptoms at early stage and biomarkers for early diagnosis are unavailable.Genetic,hormonal and reproductive factors have been reported to influence the development of ovarian cancer,but the pathogenesis is still unclear.The hypothalamic-pituitary-ovarian axis is an important neuroendocrine system and controls the female reproductive system.Gonadotropin,as an indispensable part of this axis,plays a critical role in the occurrence,development and metastasis of ovarian cancer.To identify biomarkers associated with epithelial ovarian cancer(EOC)risk in gonadotropin signaling can be beneficial to the prevention,screening,early diagnosis and treatment of EOC.Age at menarche(AAM)is an observable factor to reflect pubertal hormonal levels.It was reported that AAM was associated with ovarian cancer risk.However,the magnitude of the association for per-year effect of AAM has not been established,and the causality remains unclear.Here,after systematic meta-analyses,we performed two-sample Mendelian randomization(MR)analyses to evaluate the causal effect of AAM in EOC etiology.Methods:Data were from the EOC genome-wide association study including 1044 cases and 1172 controls of Han Chinese.After collecting gonadotropin-related gene sets in Molecular Signatures Database,we identified EOC risk-associated genetic variation in gonadotropin signaling based on summary statistics using MAGMA(v1.07).The result was validated in Europeans including 25 509 cases and 40 941 controls.For the EOC risk-associated gene,gene expression differential analyses and survival analyses were completed using public data.Assuming that the relationship between AAM and EOC risk is linear and consistent at different strata of AAM,we collected related literatures in PubMed,Embase,and Web of Science,and performed meta-analyses based on study designs with subgroup analyses based on participants’ancestry.Then we collected single nucleotide polymorphisms(SNPs)associated with AAM from AAM genome-wide association studies in Chinese.After excluding SNPs associated with other ovarian cancer-related risk factors,we calculated F statistic to evaluate the strength of instrumental variables and performed two-sample MR analyses by inverse-variance weighted methods in 1044 cases and 1172 controls of Han Chinese using the package MendelianRandomization(v0.2.2)in R(v3.3.1).And we validated the results in 29 396 cases and 68 502 controls of European ancestryResults:After evaluating the gene set related to EOC risk in gonadotropin signaling,we identified serpin family E member 1(SERPINE1)was related to EOC risk after multiple testing correction(Z=2.66,P=0.0039,P_adjust-0.0195).We validated it in Europeans(Z=1.72,P=0.0430).We observed a decrease of SERPINE1 expression in ovarian tumor tissue(log2(fold change)=-2.03,P=1.28 × 10-13)compared to ovarian normal tissue.For SNPs mapped on SERPINE1,rs1799762(odds ratio[OR]=1.20,95%confidence interval[CI]=1.06 to 1.37,P=0.0042,FDR=0.0186)and rs11178(OR=0.84,95%CI=0.75 to 0.95,P=0.0062,FDR=0.0186)were related to EOC risk in Chinese.Data in UCSC and other websites indicate rs 1799762 and rs11178 may affect the expression of SERPINE1.The associations were validated in Europeans,and in serous ovarian cancer as well.In meta-analyses,the pooled OR of EOC in case-control studies was 0.886(95%CI=0.817 to 0.961,P=0.003)and 0.961(0.930 to 0.994,P=0.019)per year increase in AAM for Asians and Europeans,respectively.No association was observed in cohort studies.In MR analyses,genetically-predicted per year older AAM was associated with EOC risk,with OR of 0.807(0.668 to 0.974,P=0.026)in Chinese and 0.937(0.898 to 0.977,P=0.003)in Europeans,respectively,and the results were similar for serous ovarian cancer.Conclusions:SERPINE1,rs1799762 and rs11178 may engage in the pathogenesis of EOC via gonadotropin signaling,and the mechanism warrants further investigation.Late AAM may decrease EOC risk,and the underlying mechanism warrants further investigation.