biostudies-literatureJiang YJiaxing Science and Technology Program-Social Development Special ProjectKey Technology Innovation Projects of JiaxingKey Research and Development Program of Zhejiang ProvinceShandong Province medical and health science and Technology project299https://www.ebi.ac.uk/biostudies/studies/S-EPMC12373740biostudies-literatureUnknown9(1)KRAS mutations drive pancreatic adenocarcinoma (PDAC) progression. This study investigates molecular heterogeneity among KRAS subtypes and their prognostic implications. This study explores KRAS mutations in PDAC, analyzing molecular heterogeneity and prognosis across our hospital cohort (SDFM, n = 113) with TCGA cohort (n = 183) and QCMG cohort (n = 383). KRAS, TP53, CDKN2A, and SMAD4 were the main mutated genes. Co-mutations of KRAS with TP53, and TP53 with CDKN2A, correlated with higher tumor mutation burden and poorer outcomes. KRAS subtypes G12D and Q16&others had worse prognosis than G12V and G12R. Combining TP53 status with KRAS subtypes improved risk stratification: high-risk patients had shorter survival (P ≤ 0.001), higher PD-L1 expression, P53 pathway alterations, fewer CD4+/CD8NPJ precision oncologyMolecular characterization and prognostic implications of KRAS mutations in pancreatic cancer patients: insights from multi-cohort analysis.PMC123737402023031112912025BS0092023C030572024BZ20002Li JZhang DZhu YTian HNiu ZGong ZXu HWang JZhao XJiang YTang MMai GCheng QYang PWang XfalseMolecular characterization and prognostic implications of KRAS mutations in pancreatic cancer patients: insights from multi-cohort analysis.KRAS mutations drive pancreatic adenocarcinoma (PDAC) progression. This study investigates molecular heterogeneity among KRAS subtypes and their prognostic implications. This study explores KRAS mutations in PDAC, analyzing molecular heterogeneity and prognosis across our hospital cohort (SDFM, n = 113) with TCGA cohort (n = 183) and QCMG cohort (n = 383). KRAS, TP53, CDKN2A, and SMAD4 were the main mutated genes. Co-mutations of KRAS with TP53, and TP53 with CDKN2A, correlated with higher tumor mutation burden and poorer outcomes. KRAS subtypes G12D and Q16&others had worse prognosis than G12V and G12R. Combining TP53 status with KRAS subtypes improved risk stratification: high-risk patients had shorter survival (P ≤ 0.001), higher PD-L1 expression, P53 pathway alterations, fewer CD4+/CD82025-01-01T00:00:00Z2025 Aug2026-05-08T06:46:47.673Z2026-04-07T23:30:36.734ZS-EPMC123737404084675410.1038/s41698-025-01087-1