Validation Of "The Dualistic Model" By The Clinicopathological Features Of Epithelial Ovarian Cancer

PART 1Validation of "the Dualistic Model" by the Clinicopathological Features of Epithelial Ovarian CancerBACKGROUND:Epithelial ovarian carcinomas are a heterogeneous group of neoplasms that exhibit a wide range of tumormorphologies and clinicalmanifestations. The pathogenesis of epithelial ovarian carcinomas influence the clinical treatment. "The Dualistic Model" of ovarian carcinogenesis has been gradually accepted. In this model, epithelial ovarian carcinomas are divided into two broad groups designated type I and type II tumors. Type I tumors are composed of low-grade serous and endometrioid carcinomas, clear cell carcinomas, mucinous carcinomas and malignant Brenner tumors. They arise in a stepwise manner from well established precursor lesions that are termed "borderline" tumors and are characterized by mutations in a number of different genes including KRAS, BRAF, PTEN. Type II tumors include high-grade serous and endometrioid carcinomas, malignant mixed mesodermal tumors (carcinosarcomas) and undifferentiated carcinomas. Type II tumors are rapidly growing, highly aggressive neoplasms. This group of tumors is characterized by mutation of TP53. The reliability of this hypothesis has not been validated by large number of clinic cases, especially in China, there is few researches for two pathway of ovarian carcinogenesis.OBJECTIVE:To validate and discuss the reliability of the dualistic model about ovarian carcinogenesis through comparing clinicopathological features of epithelial ovarian cancer among Chinese patients. METHODS:This research collected the data of 234 patients with epithelial ovarian carcinomas who have presented to the department of Gyneco-obstetrics of Zhongshan Hosipital and have undergone surgery between February 2003 and February 2011 were collected. These clinical and pathological data included age, FIGO stage, size of tumor, histopathologic classification, degree of differentiation, expression of p53 protein, ER, PR, serum CA125 value and lifetime et al. All pathological sections were reviewed by independent pathologists who unified the criteria.RESULTS:(1) In 234 patients, there were 127 (54.27%) patients with ovarian serous carcinomas, 39 (16.67%) endometrioid carcinomas,30 (12.82%) clear cell carcinomas,13 (5.56%) mucinous carcinomas,10 (4.27%) mixed carcinomas、11 (4.70%) undifferentiated carcinomas and 4(1.71%) patients with other types. The patients with stageⅠ、Ⅱ、ⅢandⅣwere 71,30,118 and 15, respectively。(2) The mean diameter of ovarian tumours in stageⅠ、Ⅱ、ⅢandⅣwas 11.63±6.06cm, 8.14±4.06cm,5.81±4.16cm, and 7.57±5.96cm, respectively. As stage increased, the mean diameter significantly decreased (P<0.01). The mean diameter with unilateral or bilateral ovarian tumors was 10.37±6.17cm or 5.44±3.11cm, the former was significantly larger than the latter (P<0.01). The size of serous tumors was the smallest among all histological types. The mean diameter of high-grade carcinomas was significantly smaller than low-grade. The survival of the patients with the average diameter of ovarian tumor≥8cm was significantly better compared with the average diameter<8cm. The patients with larger ovarian tumor had a better survival, which showed the size of ovarian tumor was associated with the nature of carcinomas.(3) The rate of strong p53 immunoreactivity were 62.7%,28.57%,38.46%and 19.23% in serous carcinomas, mucinous carcinomas, clear cell carcinomas and endometrial carcinomas, respectively. There was statistical difference between these types (p<0.01)。The rate of strong p53 immunoreactivity were respectively 35.21% and 57.26% in typeⅠand typeⅡtumors, which was a statistical difference (p<0.05). In 14 local invasive carcinomas, there were 5 cases with p53-positive stain, including 2 with strong positive. Comparison the group of p53-negative with the p53-positive, and the group of p53-negative with the p53 strong positive, the difference of survival had no statistical significance (p> 0.05).(4) The patients with bilateral ovarian tumors accounted for 23.91% and 64.08% in typeⅠand typeⅡovarian carcinomas, which was a remarkable difference (p <0.01). The cases with average diameter of ovarian tumors greater than 8cm accounted for 72.83% and 23.94% in the group of typeⅠand the typeⅡ, respectively, the former were significantly more than the latter (p<0.01). The majority of serous carcinomas were typeⅡtumors, accounting for 79.53%. TypeⅠovarian carcinomas accounted for 73.61% in early stage, whereas typeⅡaccounted for 76.07% in advanced ovarian carcinomas. Increased CA125, ER-positive and PR-positive were more common in typeⅡcompared with typeⅠ. The lifetime in typeⅠwas significantly longer than typeⅡ.(5) In univariate analysis, the lifetime between the groups that divided by unilateral or bilateral ovarian tumor, size of ovarian tumor, histological type, FIGO stage, degree of differentiation, typeⅠor typeⅡwere significant differences. Multivariate Cox proportional hazards analyses revealed that histological classification and FIGO stage were independent prognostic factors.CONCLUSIONS:There were two pathway of ovarian carcinogenesis in Chinese patients with epithelial ovarian carcinomas. Size of ovarian carcinoma and histological type were associated with two types of ovarian carcinoma which divided by "the dualistic model". However, ovarian carcinoma couldn’t be classified by the mutation of p53 gene. The dualistic model still need to be ameliorated. PART 2Discussion "the Dualistic Model" of Ovarian Carcinogenesis by Expression Profilings of miRNAs in Epithelial Ovarian CancerBACKGROUND:microRNAs (miRNAs) are a group of highly conserved non-coding RNAs. They regulate gene expression by binding to imperfect complementary sites in the 3’-untranslated region of their target messenger RNA and exert their negative regulation either by degrading the target mRNA or by post-transcriptionally repressing target-gene expression. miRNAs are involved in the regulation of multiple cellular processes, such as proliferation, apoptosis, cell-cycle, and differentiation. Abnormalities in their expression can contribute to the development of several diseases including cancer. miRNA is an important biological marker for classification of tumor and an important tool for research of pathogenesis. The results of the first part in this study showed that the classified method of the dualistic model need be improved. High-throughput analysis of the expression profilings of miRNAs would facilitate to detect new pathway of the dualistic origin of ovarian cancer and new method for classification of ovarian cancer.OBJECTIVE:Analyzing the expression profilings of miRNAs in two type of ovarian cancer by high-throughput technology for detecting miRNAs expression. To explore new molecular characteristics of ovarian cancer that can be used to divide two type of ovarian cancer.METHODS:This research collected the tissue samples of 34 patients presenting to the department of Gyneco-obstetrics of Zhongshan Hosipital and undergoing surgical treatment between August 2010 and April 2011, including 18 epithelial ovarian cancers,4 borderline epithelial ovarian tumors, and 12 normal ovarian tissues. The expression profiles of miRNAs in these fresh tissue samples were detected by a PCR-based profiling method which can identified 1200 human miRNAs. The differences of miRNAs expression between typeⅠ, typeⅡovarian cancer and borderline epithelial ovarian tumors were compared and analyzed.RESULTS:(1) Compared to normal ovarian tissue, miRNAs that expressed significantly up-regulated were miR-141、miR-200c、miR-200 and miR-21 in epithelial ovarian cancer (p<0.05), and miRNAs down-regulated were miR-195、miR-145、miR-143、miR-199a-5p、miR-125b、let-7b、miR-140-5p、miR-126、miR-10b and let-7a (p<0.05)(2) miR141、miR200c、miR200a were significantly up-regulated both in typeⅠand typeⅡovarian cancer, whereas none of them was up-regulated in borderline ovarian tumors. Some miRNAs showed significant up-regulated in all of the three sorts of ovarian tumors, including miR-195、miR-145、miR-143、miR-199a-5p、miR-125b、let-7b and miR-126. miR-140-5p was significant down-regulated in typeⅠand typeⅡovarian cancer. let-7a, let7e, miR-34c-5p were significant down-regulated both in typeⅠovarian cancer and borderline tumors, and miR-10b was significant down-regulated in typeⅡovarian cancer and borderline tumors. miR-200b was significant down-regulated only in borderline tumors.CONCLUSIONS:The differences of expressions of many miRNAs between epithelial ovarian carcinomas and normal ovarian tissues were significantly. The significant differences also existed among typeⅠ, typeⅡovarian cancers and borderline ovarian tumors miR-200 family may be an important symbol to distinguish epithelial ovarian carcinomas and ovarian borderline tumors, and let-7a、let-7e、miR-34c-5p may be used to divide typeⅠand typeⅡovarian carcinomas. The expression profiling of miRNAs may be used to distinguish type I and type II ovarian cancer.