Contributions of Low-frequency-mutated Genes in Pancreatic Tumorigenesis and Their Implications in Precision Cancer Therapy

Abstract Pancreatic cancer is an aggressive malignancy, and the limited treatment options contribute to its high mortality rate. In 2023, it ranked as the seventh leading cause of cancer-related deaths in Taiwan, with similar incidence and mortality rates highlighting the need for novel therapies. Recent next-generation sequencing studies have identified highly variable (or high-frequency mutation) genes in pancreatic cancer cells, including KRAS , TP53 , CDKN2A , and SMAD4 . Several defective or low-frequency-mutated genes have also been identified in pancreatic tumor tissues; however, their roles and contributions to pancreatic tumorigenesis remain poorly characterized. Furthermore, it remains unclear whether pancreatic cancer patients harboring these low-frequency-mutated genes are susceptible to specific targeted therapies or combination treatments. This study focuses on understanding the roles of low-frequency-mutated genes in tumorigenesis and their potential as therapeutic targets. In this study, we review relevant studies on pancreatic cancer published by our groups in the past 5 years. Using various molecular and genetic approaches, we identified the oncogenic/tumor-suppressive roles of several low-frequency-mutated genes in pancreatic tumorigenesis. These findings support the development of precision therapies targeting specific genetic alterations in pancreatic cancer. Identifying actionable targets in patients with low-frequency-mutated genes provides a molecular basis for creating tailored treatments to improve survival outcomes.