Chemotherapy-associated mutational process signature and genomic alterations associated with outcome in metastatic pancreatic cancer.

Objective: Metastatic pancreatic cancer (mPAC) carries a dismal prognosis, and effective prognostic biomarkers are critically needed. This study aims to explore novel molecular prognostic markers for mPAC from the perspective of somatic mutations.

Methods: We integrated clinical data and somatic mutation profiles from 820 mPAC patients. Prognosis-associated molecular markers were systematically explored from three perspectives: mutational process signatures, mutation activity-driven molecular subtypes, and genomic variations.

Results: The median overall survival was 11.1 months (95% CI: 9.92-12.6). Liver metastasis was the most common site and associated with worse prognosis. Tumor mutational burden (TMB) and fraction genome alteration (FGA) were favorable prognostic biomarkers. Non-negative matrix factorization identified three distinct mutational process signatures (SBS1, SBS11, and SBS29). Notably, the presence of the temozolomide-associated signature (SBS11, characterized by C > T substitutions) was associated with improved survival. Consensus clustering of mutational activity defined seven molecular subtypes, one of which (Cluster 4) demonstrated the most favorable prognosis. Genomic profiling revealed that patients harboring KRAS p.G12V mutations had the poorest survival outcomes and significantly reduced immunogenicity. Furthermore, copy-number deletions in KRAS, AKT2, and MYC were identified as biomarkers of adverse prognosis.

Conclusions: By deciphering the somatic mutational landscape of mPAC, this study identified potential molecular biomarkers associated with survival outcomes, providing a scientific foundation for prognostic prediction and informing clinical treatment strategies for mPAC.