Genomic analyses identify molecular subtypes of pancreatic cancer

Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.

Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Carcinoma, Pancreatic Ductal / classification
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / immunology
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • Gene Expression Regulation, Neoplastic
  • Gene Regulatory Networks
  • Genes, Neoplasm / genetics*
  • Genome, Human / genetics*
  • Genomics*
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-gamma / genetics
  • Histone Demethylases / genetics
  • Homeodomain Proteins / genetics
  • Humans
  • Mice
  • Mutation / genetics*
  • Nuclear Proteins / genetics
  • Pancreatic Neoplasms / classification*
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / immunology
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Prognosis
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Survival Analysis
  • Trans-Activators / genetics
  • Transcription Factors / genetics
  • Transcription, Genetic
  • Transcriptome
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Proteins / genetics
  • Zebrafish Proteins

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • DNA-Binding Proteins
  • FOXA2 protein, human
  • FOXA3 protein, human
  • Homeodomain Proteins
  • MNX1 protein, human
  • NEUROD1 protein, human
  • NR5A2 protein, human
  • Nkx2.2 protein
  • Nuclear Proteins
  • RBPJL protein, human
  • Receptors, Cytoplasmic and Nuclear
  • TP53 protein, human
  • TP63 protein, human
  • Trans-Activators
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Zebrafish Proteins
  • pancreatic and duodenal homeobox 1 protein
  • Hepatocyte Nuclear Factor 3-gamma
  • Hepatocyte Nuclear Factor 3-beta
  • Histone Demethylases
  • KDM6A protein, human

Associated data

  • GEO/GSE36924
  • GEO/GSE49149