Exploring the Role of MET Gene as a Potential Biomarker and Therapeutic Target in Ampullary Cancer

BACKGROUND: The incidence of Ampullary carcinoma (AC) has dramatically increased. Nearly 50% of patients develop recurrence indicating need for additional prognostic markers and treatment options. Emerging evidence suggests that Mesenchymal Epithelial Transition (MET) genes play a role in tumorigenesis and can be a useful therapeutic target, however, its role in AC remains unexplored. METHODS: This study investigated the methylation status using methylation specific PCR, mRNA expression using quantitative PCR and protein expression using Immunohistochemistry of the MET proto-oncogene in 61 surgically resected AC specimens and further examined its co-expression with HER2. RESULTS: Our findings revealed MET promoter hypomethylation (68.85%), increased expression of MET at mRNA (67.21%) and protein level (54%) in ACs patients. Significant correlation was observed between both hypomethylation and increased mRNA expression (P=0.026; P<0.000), and MET mRNA and protein expression (P=0.037). Further, MET expression was notably higher in early stage (P=0.003) and Intestinal-type (84.21%) than Pancreatobiliary type (PB-type) (61.76%) (P=0.199). Additionally, co-expression of MET and HER2 receptors occurred in a significant subset of cases in AC suggesting receptor tyrosine kinase convergence (P=0.014). In silico analysis of the GSE60979, dataset corroborated these findings, showing increased MET and ERBB2 (HER2) expression in tumor samples compared to normal tissues. At a median follow-up of 34 months the mean survival of AC patient was 37.3±2.5 months. CONCLUSIONS: These findings demonstrate that MET dysregulation is a recurrent molecular event in ampullary carcinoma and support further investigation of MET and HER2 co-expression as a basis for future mechanistic and therapeutic studies.