<i>ATM</i> mutations in pancreatic cancer: A real-world analysis of molecular landscapes, clinical heterogeneity, and prognostic impact.

e16376 Background: ATM is a core DNA damage repair gene. Its mutations occur in 2%-8% of pancreatic cancers, but the heterogeneity of the mutational spectrum, clinicopathological correlations, and prognostic significance remain poorly defined, especially for germline versus somatic alterations. Methods: We retrospectively analyzed 665 pathologically confirmed pancreatic cancer patients with NGS data. Patients were categorized: ATM-mutant (n=44, including somatic-only [n=35], germline-only [n=4], and co-mutant [n=5]) and ATM-wild-type (n=621). Analyses included: mutational spectrum, clinicopathological correlations, pathway enrichment (KEGG/GO/Reactome), and overall survival (OS). Statistical tests: Fisher's exact, Log-rank, and Cox models. Results: Molecular Features: ATM-mutant tumors showed a distinct co-mutation pattern, with significantly lower TP53 mutation frequency (adjusted p&lt;0.05). Germline-related ATM mutations (n=9) were enriched for CDKN2A/B inactivation (p&lt;0.05), linked to cell cycle pathways. Pathway analysis indicated reduced MAPK/RTK-RAS signaling and enriched mutations in chromatin remodeling (SWI/SNF) genes. Clinical Phenotypes: ATM-mutant patients had: (1) Higher prevalence of personal cancer history (ovarian/breast/colorectal: 16.0% vs. 5.6%, p=0.03); (2) Less local invasiveness (higher T1-2 stage: 56.8% vs. 42.4%, p=0.02). Context-Dependent Prognosis: (1) ATM status was not prognostic in the overall cohort. (2) Among initially unresectable patients, the somatic/germline co-mutant subgroup had the most favorable OS vs. wild-type and somatic-only groups (p=0.044). (3) Stratified analysis identified novel markers: In resectable ATM-mutant patients, CA199&gt;265 U/ml or RUNX1 mutation predicted poor OS (p=0.0053; p=0.0023). In stage III/IV patients, concurrent ARID1A or CDKN2A mutations were associated with shorter OS (p=0.025; p=0.0011). Genomic Stability: No significant difference in TMB among subgroups (p=0.83). Most patients were microsatellite stable. Conclusions: ATM-mutated pancreatic cancer represents a distinct subgroup with unique molecular and clinical features. Its prognostic value is highly context-dependent: somatic/germline co-mutation may be a favorable marker in unresectable disease, while RUNX1, ARID1A, CDKN2A mutations and CA199 levels enable refined risk stratification in other settings. These findings provide a new basis for personalized management of ATM-mutant pancreatic cancer.