Expression Of SET8and CyclinD1in Endometrial Diseases And Their Relationships With The Prognosis

BackgroundCorpus uteri cancer is one of the most frequently occurring female genital cancers. With the improvement of living standard, the changes of dietary structure and environmental degradation, the incidence of corpus uteri cancer has increased all over the world in recent years. In some European countries and the United States, it has almost become the most common cancer among women. Its rate in China is also increasing year by year.SET8(also known as PR-Set7/9, SETD8, KMT5A), a member of the SET domain-containing methyltransferase family specifically targeting H4K20for monomethylation, has been implicated in a diverse array of biological processes, such as controlling gene transcription, modulating replication origins,maintaining genome integrity, and regulating cell-cycle progression and development, through its histone monomethylating activity. These implications largely increase the probability that SET8involves in oncogenesis and progression of tumors. However, there has not been any explicit research about its role in tumor until now.CyclinD1, as a G1/S-specificprotein, is encoded by the CCND1gene in human beings. Being a cell-cycle regulator, CyclinDl is essential for progression through G1phase and is a candidate proto-oncogene. Mutations, amplification and over expression of CCND1gene, which can alters cell cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis. Thus, scientists pay close attention to CyclinDl recently.ObjectivesWe investigated the expression of SET8and CyclinDl in endometrial simple hyperplasia, atypicalcomplex hyperplasia (ACH), endometrial adenocarcinoma, uterine papillary serous carcinoma (ESC) and clear cell carcinoma (CCC) these five kinds of endometrial diseases by immunohistochemistryand analyzed their clinical significance;we also followed-up the patients to explore the potential of considering SET8and CyclinD1as new prognostic indicators and molecular treatment targets.Materials and MethodsWe collect endometrial lesion samples from Department of Pathology, Qilu hospital affiliated to Shandong University.These samples include27cases ofendometrialsimple hyperplasia,41cases of atypical complex hyperplasia,103cases of endometrial adenocarcinoma,21cases of uterine papillary serous carcinoma and9cases of clear cell carcinoma. Paraffin-embedded tissue blocks of the patients were sectioned and immunostained with polyclonal anti-SET8and anti-CyclinD1antibodies; Clinicopathological variables wereanalyzed with the positive expression of SET8and CyclinD1; Medical records of these201patients were gained from Medical Records Center of Qilu Hospital after getting the approval from Institutional Review Board. Follow-up survey was implemented by telephone calls and clinics to record the survival time of these201patients. Kaplan Meier analysisand multivariate Cox regressionanalysis were performed to estimate the influences of several clinicopathological and immunohistochemical covariates on the patients’ prognosis.Main ResultsSET8expression was highly expressed in ESC and CCC, with17(81%) of21ESC and7(78%) of9CCC. In contrast, the frequency of SET8expression was lesser in other lesions with6(22%) of27,22(54%) of41,69(67%) of103positive expression rates in simple hyperplasia, ACH and endometrioid carcinoma, espectively. SET8expression in simple hyperplasia was significantly lower than it in endometrial malignancies (p<0.005), SET8staining was correlated with invasion and metastasis (p<0.005). CyclinDl was significantly overexpressed in ACH, endometrioid carcinoma and CCC. The positive signaling of CyclinDl was showed less than40%in simple hyperplasia and ESC. The high expression of CyclinD1was observed in metastasis carcinoma group more significantly than non-metastasis carcinoma group. Kaplan Meieranalysis denoted patients with SET8and (or) CyclinDl expression had significantly poor prognosis than the patients without their staining (p<0.05). Multivariate Cox regression analysis demonstrated that SET8and (or) CyclinD1expression, as crucial as metastasis, was a risk marker for survival.Discussions and SuggestionsSET8, as a newly identified nuclear marker, seems closely associated with endometrial neoplastic lesions. SET8exhibits a promising potential to predict prognosis of patients with endometrial carcinoma. Therefore, SET8may become a useful prognostic marker in the assessment of endometrial cancers. CyclinDl also exhibited a promising potential to predict the prognosis of patients with endometrial carcinoma. However, the statistical analysis demonstrated that CyclinDl exhibited a poor ability to differentiate neoplastic lesions from non-neoplastic lesions; thus, the application of CyclinDl only is not so credible fordifferentiation between benign and malignant lesions. Additionally, the results prompted the possibility of consideringSET8and CyclinDl as new prognostic marker and molecular therapeutic targets for endometrial diseases.