This review discusses the significance of TP53, CDKN2A, SMAD4, and KRAS in pancreatic cancer. These genes play critical roles in tumor suppression, progression, and prognosis. TP53 mutations are common in pancreatic ductal adenocarcinomas (PDAC) and are associated with poor prognosis. CDKN2A mutations are also prevalent in pancreatic tumors and are linked to increased cancer risk. SMAD4 is involved in TGF-β signaling and its loss contributes to tumor progression. KRAS mutations are the most frequent in PDAC and are essential for tumor growth. The review highlights the importance of genomic analysis for risk assessment, early detection, and personalized treatment. It also explores potential targeted therapies based on molecular signatures. The findings emphasize the need for further research to develop more effective therapeutic strategies for pancreatic cancer.This review discusses the significance of TP53, CDKN2A, SMAD4, and KRAS in pancreatic cancer. These genes play critical roles in tumor suppression, progression, and prognosis. TP53 mutations are common in pancreatic ductal adenocarcinomas (PDAC) and are associated with poor prognosis. CDKN2A mutations are also prevalent in pancreatic tumors and are linked to increased cancer risk. SMAD4 is involved in TGF-β signaling and its loss contributes to tumor progression. KRAS mutations are the most frequent in PDAC and are essential for tumor growth. The review highlights the importance of genomic analysis for risk assessment, early detection, and personalized treatment. It also explores potential targeted therapies based on molecular signatures. The findings emphasize the need for further research to develop more effective therapeutic strategies for pancreatic cancer.