biostudies-literatureVarghese AMU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)U.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHS466-477https://www.ebi.ac.uk/biostudies/studies/S-EPMC11835752biostudies-literatureUnknown31(2)Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present with advanced disease and are treated with cytotoxic therapy. Genomic biomarkers prognostic of disease outcomes have been challenging to identify. Herein leveraging a cohort of 2,336 patients spanning all disease stages, we characterize the genomic and clinical correlates of outcomes in PDAC. We show that a genomic subtype of KRAS wild-type tumors is associated with early disease onset, distinct somatic and germline features, and significantly better overall survival. Allelic imbalances at the KRAS locus are widespread. KRAS mutant allele dosage gains, observed in one in five (20%) KRAS-mutated diploid tumors, are correlated with advanced disease and demonstrNature medicineClinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival.PMC11835752P30 CA008748P50 CA257881-01A1CA257881-01A1CA008748P50 CA257881R01 CA227534Kelsen DPVarghese AMSchattner MABandlamudi CO'Reilly EMFong CPerry MAChakravarty DPark WWei ACErakky ASchultz NChou JFYu KHNandakumar SBerger MFMehine MStadler ZKMandelker DMuldoon DBasturk OBalogun FBrannon ARNguyen BZucker ACapanu MVakiani EJarnagin WRIacobuzio-Donahue CAfalseClinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival.Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRAS exon 2 mutations. Most patients with PDAC present with advanced disease and are treated with cytotoxic therapy. Genomic biomarkers prognostic of disease outcomes have been challenging to identify. Herein leveraging a cohort of 2,336 patients spanning all disease stages, we characterize the genomic and clinical correlates of outcomes in PDAC. We show that a genomic subtype of KRAS wild-type tumors is associated with early disease onset, distinct somatic and germline features, and significantly better overall survival. Allelic imbalances at the KRAS locus are widespread. KRAS mutant allele dosage gains, observed in one in five (20%) KRAS-mutated diploid tumors, are correlated with advanced disease and demonstr2025-01-01T00:00:00Z2025 Feb2026-06-02T20:15:07.65Z2025-04-07T07:54:41.51ZS-EPMC118357523975396810.1038/s41591-024-03362-3