Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival

Nearly all pancreatic adenocarcinomas (PDAC) are genomically characterized by KRASexon 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 KRASwild-type tumors is associated with early disease onset, distinct somatic and germline features, and significantly better overall survival. Allelic imbalances at the KRASlocus are widespread. KRASmutant allele dosage gains, observed in one in five (20%) KRAS-mutated diploid tumors, are correlated with advanced disease and demonstrate prognostic potential across disease stages. With the rapidly expanding landscape of KRAStargeting, our findings have potential implications for clinical practice and for understanding de novo and acquired resistance to RAS therapeutics.