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

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.

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.

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.

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.