Genomic analyses identify molecular subtypes of pancreatic cancer

P Bailey, D K Chang, K Nones, A L Johns, A M Patch, M C Gingras, D K Miller, A N Christ, T J Bruxner, M C Quinn, C Nourse, L C Murtaugh, I Harliwong, S Idrisoglu, S Manning, E Nourbakhsh, S Wani, L Fink, O Holmes, V Chin, M J Anderson, S Kazakoff, C Leonard, F Newell, S Wood, Q Xu, P J Wilson, N Cloonan, K S Kassahn, D Taylor, K Quek, A Robertson, L Pantano, L Mincarelli, L N Sanchez, L Evers, J Wu, M Pinese, M J Cowley, M D Jones, E K Colvin, A M Nagrial, E S Humphrey, L A Chantrill, A Mawson, J Humphris, A Chou, M Pajic, C J Scarlett, A V Pinho, M Giry-Laterriere, I Rooman, J S Samra, J G Kench, J A Lovell, N D Merrett, C W Toon, K Epari, N Q Nguyen, A Barbour, N Zeps, K Moran-Jones, N B Jamieson, J S Graham, F Duthie, K Oien, J Hair, R Grutzmann, A Maitra, C A Iacobuzio-Donahue, C L Wolfgang, R A Morgan, R T Lawlor, V Corbo, C Bassi, B Rusev, P Capelli, R Salvia, G Tortora, D Mukhopadhyay, G M Petersen, Initiative Australian Pancreatic Cancer Genome, D M Munzy, W E Fisher, S A Karim, J R Eshleman, R H Hruban, C Pilarsky, J P Morton, O J Sansom, A Scarpa, E A Musgrove, U M Bailey, O Hofmann, R L Sutherland, D A Wheeler, A J Gill, R A Gibbs, J V Pearson, N Waddell, A V Biankin, S M Grimmond
January 2016
PDF DOI

Abstract

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, 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 TP63N 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.

Type
Journal article
Publication
Nature
*Genomics Animals Basic Helix-Loop-Helix Transcription Factors/genet Carcinoma Pancreatic Cell Line Tumor DNA Methylation DNA-Binding Proteins/genetics Ductal/classification/genetics/immunology/metaboli Gene Expression Regulation Neoplastic Gene Regulatory Networks Genes Neoplasm/*genetics Genome Human/*genetics 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/*genetics/imm 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

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