Convergence of KRAS Mutations and MTAP Loss in Pancreatic Cancer: Genomic Landscape and Clinical Implications

PURPOSE: Comprehensive genomic profiling has prognostic and predictive value for patients with pancreatic adenocarcinoma (PAAD). EXPERIMENTAL DESIGN: We reviewed clinical and molecular data from 4,009 samples from patients who had undergone the BostonGene Tumor Portrait test between October 28, 2021, and October 8, 2024, and 2,181 samples from the BostonGene PAAD meta-cohort, collected from various data hosts and processed by BostonGene automated pipelines. RESULTS: In this high-purity PAAD cohort, 24% harbor homozygous methylthioadenosine phosphorylase (MTAP) deletion, and the co-occurrence of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and MTAP loss was common (18.9% of all PAADs). This association identified a subgroup with worse survival outcomes. MTAP-deficient tumors harbor more fibrotic, less immune-enriched microenvironments and have shorter survival. Within the comutated tumors, the most frequently detected KRAS variants were G12D, G12V, and G12R, with the last one slightly more related to immune-enriched tumor microenvironment features than the other KRAS variants. CONCLUSIONS: Comprehensive genomic profiling is essential for patients with PAAD and carries both prognostic and predictive values. MTAP loss in KRAS-mutant PAAD represents a subgroup of immune-excluded PAADs with a poor prognosis.