Genomic analyses identify molecular subtypes of pancreatic cancer.

TitleGenomic analyses identify molecular subtypes of pancreatic cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsBailey, P, Chang, DK, Nones, K, Johns, AL, Patch, A-M, Gingras, M-C, Miller, DK, Christ, AN, Bruxner, TJC, Quinn, MC, Nourse, C, L Murtaugh, C, 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, U-MHagbo, Hofmann, O, Sutherland, RL, Wheeler, DA, Gill, AJ, Gibbs, RA, Pearson, JV, Waddell, N, Biankin, AV, Grimmond, SM
Corporate AuthorsAustralian Pancreatic Cancer Genome Initiative
JournalNature
Volume531
Issue7592
Pagination47-52
Date Published2016 Mar 03
ISSN1476-4687
KeywordsAnimals, Basic Helix-Loop-Helix Transcription Factors, Carcinoma, Pancreatic Ductal, Cell Line, Tumor, DNA Methylation, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Gene Regulatory Networks, Genes, Neoplasm, Genome, Human, Genomics, Hepatocyte Nuclear Factor 3-beta, Hepatocyte Nuclear Factor 3-gamma, Histone Demethylases, Homeobox Protein Nkx-2.2, Homeodomain Proteins, Humans, Mice, Mutation, Nuclear Proteins, Pancreatic Neoplasms, Prognosis, Receptors, Cytoplasmic and Nuclear, Survival Analysis, Trans-Activators, Transcription Factors, Transcription, Genetic, Transcriptome, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Zebrafish Proteins
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.
DOI10.1038/nature16965
Alternate JournalNature
PubMed ID26909576
Grant List21139 / CRUK_ / Cancer Research UK / United Kingdom
12946 / CRUK_ / Cancer Research UK / United Kingdom
MR/N005813/1 / MRC_ / Medical Research Council / United Kingdom
20409 / CRUK_ / Cancer Research UK / United Kingdom
A12481 / CRUK_ / Cancer Research UK / United Kingdom
17263 / CRUK_ / Cancer Research UK / United Kingdom
22533 / CRUK_ / Cancer Research UK / United Kingdom
P50 CA062924 / CA / NCI NIH HHS / United States
A18076 / CRUK_ / Cancer Research UK / United Kingdom
RIF2015_A06_JAMIESON / PANCREATICCANUK_ / Pancreatic Cancer UK / United Kingdom
C29717/A17263 / CRUK_ / Cancer Research UK / United Kingdom
11650 / CRUK_ / Cancer Research UK / United Kingdom
103721/Z/14/Z / WT_ / Wellcome Trust / United Kingdom

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