Concurrent TP53 and ARID1A Mutations Are Associated with Adverse Survival Outcomes and Distinct Molecular Signatures in Pancreatic Ductal Adenocarcinoma

Background/Objectives: Genomic profiling has become central to understanding prognosis in pancreatic ductal adenocarcinoma (PDAC), yet the canonical drivers KRAS, TP53, SMAD4, and CDKN2A do not fully explain survival heterogeneity, and the prognostic impact of co-occurring alterations remains incompletely characterized. Methods: We performed integrated genomic, transcriptomic, proteomic, phosphoproteomic, and immune deconvolution analyses of publicly available PDAC datasets. Un-supervised clustering of survival extremes in MSK-IMPACT identified a subgroup enriched for concurrent TP53 and ARID1A mutations. Results: ARID1A was mutated in 7–8% of tumors across cohorts, of which 66–72% were TP53 co-mutated. Co-mutated tumors had the shortest overall survival of any subgroup (median 21.4 vs. 34.8 months in non-co-mutated tumors; log-rank p < 0.001), a pattern that persisted in the full MSK-IMPACT cohort and in independent multi-cohort validation. Transcriptomic analysis showed enrichment of MYC target, EMT, and E2F/cell-cycle programs alongside coordinated suppression of oxidative phosphorylation and lipid metabolism, with EMT tracking more closely with ARID1A mutation and cell-cycle programs with TP53 mutation. Immune deconvolution identified reduced plasma cell infiltration in co-mutated tumors. Proteomic profiling recapitulated EMT, hypoxia, and TNF-α/NF-κB enrichment, and kinase-substrate enrichment analysis inferred increased mTOR and MEK1 activity. Conclusions: These findings are hypothesis-generating and suggest that TP53 + ARID1A co-mutated PDAC represents a prognostically distinct subtype, with candidate therapeutic vulnerabilities in MAPK, mTOR, and proteostasis pathways that warrant validation in larger cohorts and functional studies.