Clinicogenomic landscape of pancreatic adenocarcinoma identifies KRAS mutant dosage as prognostic of overall survival
Anna M. Varghese, Maria Perry, Joanne F. Chou, Subhiksha Nandakumar, Daniel M. Muldoon, Amanda Erakky, Amanda Zucker, Christopher J. Fong, Miika Mehine, Bastien Nguyen, Olca Baştürk, Fiyinfolu Balogun, David P. Kelsen, A. Rose Brannon, Diana Mandelker, Efsevia Vakiani, Wungki Park, Kenneth H. Yu, Zsofia K. Stadler, Mark Schattner, William R. Jarnagin, Alice C. Wei, Debyani Chakravarty, Marinela Capanu, Nikolaus Schultz, Michael F. Berger, Christine A. Iacobuzio–Donahue, Chaitanya Bandlamudi, Eileen M. O’Reilly
Abstract
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 demonstrate prognostic potential across disease stages. With the rapidly expanding landscape of KRAS targeting, our findings have potential implications for clinical practice and for understanding de novo and acquired resistance to RAS therapeutics. Analyses of clinical and genomic data from a cohort of 2,336 patients with pancreatic adenocarcinoma find that KRAS dosage gains are a hallmark of disease progression and are predictive of poor outcomes across different disease stages.