1. Genomic analyses identify molecular subtypes of pancreatic cancer.
- Author
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Bailey P, Chang DK, Nones K, Johns AL, Patch AM, Gingras MC, Miller DK, Christ AN, Bruxner TJ, Quinn MC, Nourse C, Murtaugh LC, Harliwong I, Idrisoglu S, Manning S, Nourbakhsh E, Wani S, Fink L, Holmes O, Chin V, Anderson MJ, Kazakoff S, Leonard C, Newell F, Waddell N, Wood S, Xu Q, Wilson PJ, Cloonan N, Kassahn KS, Taylor D, Quek K, Robertson A, Pantano L, Mincarelli L, Sanchez LN, Evers L, Wu J, Pinese M, Cowley MJ, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chantrill LA, Mawson A, Humphris J, Chou A, Pajic M, Scarlett CJ, Pinho AV, Giry-Laterriere M, Rooman I, Samra JS, Kench JG, Lovell JA, Merrett ND, Toon CW, Epari K, Nguyen NQ, Barbour A, Zeps N, Moran-Jones K, Jamieson NB, Graham JS, Duthie F, Oien K, Hair J, Grützmann R, Maitra A, Iacobuzio-Donahue CA, Wolfgang CL, Morgan RA, Lawlor RT, Corbo V, Bassi C, Rusev B, Capelli P, Salvia R, Tortora G, Mukhopadhyay D, Petersen GM, Munzy DM, Fisher WE, Karim SA, Eshleman JR, Hruban RH, Pilarsky C, Morton JP, Sansom OJ, Scarpa A, Musgrove EA, Bailey UM, Hofmann O, Sutherland RL, Wheeler DA, Gill AJ, Gibbs RA, Pearson JV, Waddell N, Biankin AV, and Grimmond SM
- Subjects
- 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, Hepatocyte Nuclear Factor 3-beta genetics, Hepatocyte Nuclear Factor 3-gamma genetics, Histone Demethylases genetics, Homeobox Protein Nkx-2.2, Homeodomain Proteins genetics, Humans, Mice, Nuclear Proteins 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, Genes, Neoplasm genetics, Genome, Human genetics, Genomics, Mutation genetics, Pancreatic Neoplasms classification, Pancreatic Neoplasms genetics
- 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.
- Published
- 2016
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