Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine. [Display omitted] •Multi-platform study of 150 pancreatic cancers accounting for neoplastic cellularity•Identify KRAS mutational heterogeneity and alternate drivers in KRAS wild-type tumors•Identify proteomic subtypes with prognostic significance and therapeutic implications•Integrated analysis of mRNA and non-coding RNA suggests consensus subtypes This TCGA study reveals the complex molecular landscape of PDAC, with a small number of tumors carrying multiple KRAS mutations, KRAS wild-type PDACs harboring alterations in other RAS pathway genes or alternate oncogenic drivers, and integrated RNA and protein subtypes indicating clinically significant subsets of disease.