The Mutations And Protein Expressions Of PTEN And P53 Genes In Malignant Transformation Of Endometriosis

Background and Objective Recent studies have demonstrated that endometriosis has the potential of malignant transformation.However,the molecular mechanisms underlying malignant transformation of endometriosis are rarely understood.To clarify the roles of alterations of PTEN and p53 genes in the process of malignant transformation of endometriosis,in the present study we investigated the mutations and aberrant protein expressions of PTEN and p53 genes in the endometriosis-associated ovarian cancers and atypical endometriosis.Methods Twenty-three endometriosis associated ovarian cancers(EAOCs),ten atypical hyperplasia endometriosis(aEMs) of ovary and 20 typical endometriosis tissues were used in the present study.Of the 23 EAOC samples,nine were endometrioid ovarian cancers coexisting with endometriosis,fourteen were clear cell ovarian cancers coexisting with endometriosis,and 4 of them fulfill the diagnostic criteria of malignant transformation of endometriosis by Sampson and Scott.The atypical endometriosis fulfill the diagnostic criteria of the LaGrenade and Silverberg.The mutations of exons 2-8 of PTEN gene and exons 5-11 of p53 gene were investigated using polymerase chain reaction and DNA sequencing analysis.The protein expressions of PTEN and p53 genes were detected using immunohistochemistry PV-9000 method.Results1.PTEN mutations occurred in eight of 23 EAOCs and the mutant rate was 34.8%. Of them 4 samples were found to have p53 mutations.The mutant rate was 17.4%. Moreover,one sample demonstrated PTEN and p53 mutation simultaneously.Two samples which fulfill the criteria of endometriosis malignancy demonstrated PTEN or p53 mutation respectively.The rates of PTEN gene and p53 gene mutation of EAOCs were significantly higher than those of aEMs(0%) and EMT(0%).There was significant difference between EAOCs and EMT(P<0.01,P<0.05).On the contrary,there was no significant difference when compared to aEMs(P>0.05).There was no relationship between the rates of PTEN/p53 mutation of EAOCs and age difference,histological type, surgical-pathological stage,differentiated grade and whether there was metastasis(P> 0.05).However,the mutant rate of PTEN of EAOCs which were at early pathological stage,well differentiated was much higher than that at late surgical-pathological stage and poorly differentiated.And p53 showed the opposite trend.2.On the same slide in EAOCs group,endometriosis epithelial linings and cancers tissues demonstrated same protein expression pattern both in PTEN and p53 genes.Of 23 EAOC cases,eighteen(78.26%) and four(17.39%) demonstrated PTEN and p53 protein expression deletions,respectively.In EMT and aEMs groups,the PTEN protein expression deletion rates were 5%and 20%respectively while p53 protein expression deletions were 85%and 70%respectively.There was significant difference when comparing EAOC with EMT or aEMs(P<0.05).The rates of protein expression of PTEN/p53 in EAOC were not related to age or histological type(P>0.05),but closely related to surgical-pathological stage,differentiated grade and metastasis(P<0.05).The rate of protein expression deletion of PTEN of EAOC which were at early surgical-pathological stage,well differentiated and not accompanied metastasis was significantly lower than those at late surgical-pathological stage,poorly differentiated and accompanied metastasis.Contrary to PTEN,p53 demonstrated a trend that the rate of protein expression deletion of EAOCs which were at early surgical-pathological stage, well differentiated and not accompanied metastasis was significantly higher than those at late surgical-pathological stage,poorly differentiated and accompanied metastasis.The protein expressions of PTEN and p53 genes were negatively correlated(r_s=-0.593, P=0.003).Conclusion1.The mutations and aberrant protein expressions of PTEN gene and p53 gene may play important roles during the malignant transformation of endometriosis.2.The rates of PTEN gene and p53 gene mutations of EAOCs were significantly higher than those of aEMs and EMT,which suggested that mutations of these two genes may be involved in the process of malignant transformation of endometriosis.More frequently,PTEN gene mutation occurred in cases at early surgical-pathological stage and well differentiated tissues.On the contrary,p53 gene mutation more frequently occurred in cases at late surgical-pathological stage,poorly differentiated tissues.PTEN mutation may be an early event but p53 mutation may be a late event during the progression of endometriosis malignancy.3.The protein expression deletion rates of PTEN in EAOCs were higher than those in EMT and aEMs groups,while p53 protein expression deletion rates in EAOCs were lower than those in EMT and aEMs groups.Moreover,on the same slide of EAOCs, endometriosis epithelial linings and cancers tissues demonstrated same protein expression pattern both in PTEN and p53 genes,suggesting that aberrant protein expressions of these two genes may be involved in the process of malignancy of endoemetriosis.