BRAF Mutations And Expressions In Esophageal And Cardiac Cancers

Objectives: gastric cardiac adenocarcinoma(GCA) is a common tumor in our country. Its main treatment is still surgical resection by far, the 5-year survival rate of surgical resection was just 17.6% to 25.1%. The 5-year survival rate of palliative resection was 8.0%.esophageal cancer is the sixth most common cause of cancer woldwide and the incidence rates vary according to sex, counteries, and histological types. esophageal squamous cell carcinoma(ESCC) is the major histological type of esophageal cancer in East Asian countries and its the most aggressive malignant tumous. esophageal cancer is a highly aggressive disease and the 5-years surrvival rate is approximately 15%. approximately 50% of patients show distant metastasis and half of the remaining patients who initially pressent with locoregional disease eventually develop distant metastase. in case of metastatic disease, median survival is less than a year despite of palliative chemotherapy. Despite remarkable advances in multimodal therapies in GCA and ESCC, patient prognosis remains poor, even for those whose carcinomas have been completely resected. the limited improvement in treatment outcomes by conventional therapies urged us to seek innovative strategies for treating GCA and ESCC.The RAS protein regulate cell proliferation, survival and differentiation by activating a number of downstream effectors, including RAF protein kinase. Once activated, RAF stimulates a signaling cascade involving the MEK/ERK pathway. BRAF, a serine-threonine kinase, is one of the three RAF protein kinase family members(ARAF, BRAF and CRAF). The BRAF proto-oncogene has recently been the focus of intensive research, as its mutation constitutively activates RAF/MEK signaling, a major driver of carcinogenesis in various malignancies, most notably in melanoma, colon cancer, and papillary thyroid cancer, The most common BRAF mutation is a substitution of glutamic acid for valine in codon 600(V600E).Oncogenic mutations such as BRAF occur across diverse tumor types. In this study we examed 91 tissue specimens obtained from patients who were pathologically confirmed with GCA or ESCC. BRAF expressions were detected by using immunohistochemistry in these 91 GCA and ESCC specimens, and the corelation between expression of BRAF and patients clinical characteristics were analyzed.Methods: A total of 46 consecutive patients with GCA and 45 with ESCC who were undergoing curative resection at Fourth Hospital of Hebei Medical University thoracic surgery department between December 2013 to December 2014 were enrolled in this study. At the same time, far tumor tissues corresponding to fresh cancer tissue specimens(5cm above the edge of cancer tissue)as a control group. All specimens grouped by patients’ gender, age, pathology types, degree of differentiation and TNM stage. The frequency of BRAF mutations were examed using a nonbiased database of 46 resected GCA and 45 resected ESCC and a high-thoughput pyrosequencing assay. Immunohistochemistry was uesd to detect the expression of BRAF protein in the tumor group and the far tumor group. All analyses were performed using SPSS13.0 statistical software. we analysised the positive expression of BRAF in cancer tissues and far cancer tissues. We also investigated the relationship between the BRAF positive expressions in GCA/ESCC and the clinical characteristics. P<0.05 was considered statistically significant.Result:1 BRAF mutations in GCA and ESCCA total of 3 GCA tumor samples harboring 1 different BRAF mutation(V600E) was detected in all 46 GCA tumor samples. mutations in codon 600 were found in 3 GCA patients. Unfortunately, there is no mutation could be detected in our 45 ESCC samples.2 The expression of BRAF in GCA and ESCCImmunohistochemistry results showed BRAF protein is in the cytoplasm and appeared as brown or brownish yellow particles. The statistics data showed that the positive expression rate of BRAF protein in GCA is 47.82% and the far cancer positive expression rate is 6.52%. The difference between both groups have statistically significant in GCA(P<0.05). Similar results were detected in ESCC group. Our results showed positive expression rate of BRAF protein in ESCC tumor group is 62.22% and in far tumor group positive expression rate is 8.89%. there were significant differences between ESCC tumor and far tumor groups(P<0.05).The relationship between BRAF protein expression and clinical features in GCA and ESCC are analyised. our results showed that the positive expression of BRAF protein were 22 cases in all 46 cases of GCA. The overall positive rate was 47.82%. Distributed: male 50.0%,female 37.5%. Patients over 60 years of age(including 60 year old) 60.0%,38.5% of patients under 60 years old patients. Ⅰstage 18.2%,Ⅱstage 33.3%,Ⅲstage 75.0%. Without lymph node metastasis is 14.3%,and with lymph node metastasis is 62.5%. Statistical analysis show that the BRAF protein expression have no relationship in gender, age,and lymph node metastasis. However,BRAF protein expression have closely relationship with TNM stage(Z=-3.242,P<0.05)and lymph node metastasis(χ2=9.073, P<0.05). The positive expressions of BRAF protein were 28 cases in all 45 cases of ESCC. The overall positive rate was 62.22%. Distributed: male 55.6%,female 72.2%. Patients over 60 years of age(including 60 year old) 53.6%,76.5% of patients under 60 years old patients. Ⅰstage 21.4%,Ⅱstage 50.0%,Ⅲ stage 88.2%. Without lymph node metastasis is 40.9%,and with lymph node metastasis is 82.6%. Statistical analysis show that the BRAF protein expression have closely relationship with TNM stage(Z=-3.718, P<0.05)and lymph node metastasis(χ2=8.318,P<0.05).Conclusion:1 BRAF mutations in GCA and ESCCWe further investigated the behavior of BRAF mutation with V600 E compared to BRAF without mutation in GCA samples. We found that V600 E was associated with lymph node metastasis and worse TNM stage. Our results showed V600 E mutation of BRAF as a prognostic factor associated with more aggressive behavior in GCA.2 The expression of BRAF in GCA and ESCCThe numbers of BRAF positive expression samples were significantly increased in GCA and ESCC cancer group comparing with far cancer tissues. Patients’ TNM stage and lymph node metastasis were significantly worse for patients with positive versus negative expression of BRAF in both GCA and ESCC. There were no significant differences between the positive and negative expression of BRAF for other characteristics, cluding gender, age and degree of differentiation. Our data suggest that BRAF may cause the GCA and ESCC, and work as a diagnosis.