title: Genomic analyses identify molecular subtypes of pancreatic cancer.
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.
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
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authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
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authors.initials: SM
authors.lastname: Grimmond
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000145:classification / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D052138:Genes, Neoplasm / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000235:genetics; D056466:Histone Demethylases / Q000235:genetics; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000145:classification* / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D051543:Hepatocyte Nuclear Factor 3-gamma; D056466:Histone Demethylases; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D029961:Zebrafish Proteins; C496502:FOXA2 protein, human; C496505:FOXA3 protein, human; C490003:MNX1 protein, human; C093970:NEUROD1 protein, human; C000715631:NKX2-2 protein, human; C082631:NR5A2 protein, human; C000715627:Nkx2-2 protein, mouse; C105571:RBPJL protein, human; C495901:TP53 protein, human; C115051:TP63 protein, human; C000715630:nkx2.2b protein, zebrafish; C084010:pancreatic and duodenal homeobox 1 protein; C523998:KDM6A protein, human