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

Genomic analyses identify molecular subtypes of pancreatic cancer.

Collaborators (149)

Biankin AV, Johns AL, Axford CJ, Mawson A, Chang DK, Scarlett CJ, Brancato MA, Simpson SH, Martyn-Smith M, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Mead R, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Watson C, Steinmann A, Lee HC, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu C, Nones K, Fink J, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Bailey P, Quinn M, Nagaraj S, Kazakoff S, Waddell N, Krisnan K, Quek K, Wood D, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Asghari R, Merrett ND, Pavey D, Das A, Cosman PH, Ismail K, O'Connnor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Gairdner C, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O'Rourke TJ, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Mountain A, Scarpa A, Lawlor RT, Sperandio N, Bonizzato G, Grimaldi S, Cantù C, Merlini P, Turri G, Pea A, Pedrazzani C, Ruzzenente A, Gobbo S, Martignoni G, Girelli R, Biankin AV, Grimmond SM, Chang DK, Musgrove EA, Jones MD, Nourse C, Jamieson NB, Graham JS, Biankin AV, Chang DK, Jones MD, Jamieson NB, Graham JS.


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.

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