Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma

Cancer Cell. 2017 Aug 14;32(2):185-203.e13. doi: 10.1016/j.ccell.2017.07.007.

Abstract

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.

Keywords: KRAS; PDAC; RPPA; TCGA; genomics; heterogeneity; miRNA; molecular subtypes; pancreatic cancer; tumor cellularity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / metabolism
  • DNA Methylation
  • Epigenesis, Genetic / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genomics / methods
  • Humans
  • Mutation / genetics*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Proteome / analysis*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Transcriptome / genetics*

Substances

  • KRAS protein, human
  • Proteome
  • Proto-Oncogene Proteins p21(ras)