Mcm2 Protein Expression In The Carcinogenesis Of Cardiac Carcinoma And Its Prognostic Significance

BackgroundMinichromosome maintenance proteins (MCMs) are members of the pre-replicative complex that is essential for eukaryotic DNA replication. They are only present within the nucleus throughout the cell cycle, but rapidly downregulated in differentiated cells. Recent studies have proposed that Mcm2 protein may be sensitive proliferation markers and may serve as novel biomarkers for prognostication and diagnosis of various pre-malignant and malignant lesions. Mcm2 protein expression in the cardiac tissue is lack of systematic research.ObjectiveThe aim of this study is to determine the pattern and frequency of Mcm2 protein expression in gastric cardia normal mucosa, hyperplasia mucosa, dysplasia mucosa and cancer, and to analysis the relationship between Mcm2 protein expression and clinicopathological parameters in gastric cardia cancer and its impact on prognostic survive. Also, the expression of Mcm2 protein is also compared with the expression of PCNA and Ki-67 protein, another kind of markers for cell proliferation, to determine which is a better marker for gastric cardia cancer and to provide theoretical evidence for clinicopathological diagnosis and evaluation of prognosis MaterialsWe collected resection specimens from 180 patients with cardiac carcinoma from October 2000 to October 2007 who had undergone curative resection in Cancer Hospital of Shantou University Medical College. Among the 180 patients with cardiac carcinoma, 133 cases have complete follow-up data. 126 cases of 133 patients followed-up for no less than 5 years. In all, 5-year follow-up was 94.7%. 57 cases of Cardia mucosa specimens: 10 cases of normal mucosa, 17 cases of simple hyperplasia, 30 cases of dysplasia mucosa. Normal cardia specimens resected from autopsy cases of non-cardia diseasesMethodsMcm2,Ki-67 and PCNA protein expression were detected by immunohistochemical Envision Labelled Peroxidase System Two-Step Method. Then, the sections were taken nine images randomly using Leica DMRXA2 Almighty microscope and Leica IM50 image acquisition system and calculated the labeling index of Mcm2, Ki-67 and PCNA protein expression.Result1. Mcm2 expression in normal cardia mucosa and simple hyperplasia is confined to the basal 1/3 to 1/2 of cardiac gland, but no expression in surface cells of gastric cardia mucosa or interstitial cells. In dysplasia mucosa and cardia carcinoma, Mcm2 expression is seen throughout epithelium, including in surface gastriccytes. The gastric cardia mucosa from normal, hyperplasia, dysplasia to carcinoma, the LI of Mcm2, Ki-67and PCNA get higher gradually, and there are significant difference(P<0.001). .In dysplasia mucosa and cancer, the LI of Mcm2 was higher than Ki-67 and PCNA, and expression layer was higher.2. Epidemiology diagnostic test evaluation for Ki-67, Mcm2 and PCNA displayed that the LI of Mcm2 in gastric cardia precancerous change (dysplasia): sensitivity is 90.0%, specificity is 63.0%, accuracy is 77.2%, positive predictive value is 73.0%, negative predictive value is 87.0%, and each was much higher than Ki-67 and PCNA.3. There is no statistical significance between the LI of Mcm2 and some clinicopathological characteristics such as age, sex, dimension and histopathology (P>0.05). A significant association is also demonstrated between the LI of Mcm2 and TNM stage, lymph node metastases, the grade of gastric cardia cancer(P<0.05). Compared with the PCNA and Ki-67, the LI of Mcm2 protein is higher (P<0.05), and it is a better marker related with the grade of gastric cardia cancer.4. In univariate analysis (Kaplan-Meier), the OSR and DFSR of the low group expressed Mcm2, Ki-67and PCNA are higher than that of the high expression group, respectively. Ten significant prognostic factors were chosen for multivariate analysis (Cox proportional hazard model). They were sex, age, chemotherapy, dimension, TNM stage, T stage, N stage, LI (Mcm2), LI (PCNA) and LI (Ki-67). The result shows that sex (P=0.014, OR=1.901), TNM stage (P=0.000, OR=2.028), chemotherapy (P=0.018, OR=0.499) and LI (Mcm2) (P=0.012, OR=3.421) are independent prognostic factors for overall survival.Conclusion1. These data support the evidence that Mcm2 may serve as a reliable proliferation marker in gastric cardia tissue, and according to the pattern and LI of Mcm2 expression, it is feasible to discriminate between normal tissue and dysplasia, cancer.2. For the diagnosis of dysplasia, the sensitivity, specificity, accuracy, positive predictive value, negative predictive value, Mcm2 is better than PCNA and Ki-67.3. It implies that Mcm2 has potential to be a better diagnostic marker for gastric cardia cancer than other markers such as PCNA Ki-67. In addition, as LI of Mcm2 is related with the grade of gastric cardia cancer, it can predict the degree of differentiation in gastric cardia cancer, which helps to predict the prognosis.4. Mcm2 may be an independent prognostic factor for gastric cardia carcinoma. This will help to accurately determine the survival probability of cardiac cancer patients and to provide a theoretical basis for individual treatment of cardiac cancer.