Genomic analyses identify molecular subtypes of pancreatic cancer.

Authors:
Peter Bailey David K Chang Katia Nones Amber L Johns Ann-Marie Patch Marie-Claude Gingras David K Miller Angelika N Christ Tim J C Bruxner Michael C Quinn Craig Nourse L Charles Murtaugh Ivon Harliwong Senel Idrisoglu Suzanne Manning Ehsan Nourbakhsh Shivangi Wani Lynn Fink Oliver Holmes Venessa Chin Matthew J Anderson Stephen Kazakoff Conrad Leonard Felicity Newell Nick Waddell Scott Wood Qinying Xu Peter J Wilson Nicole Cloonan Karin S Kassahn Darrin Taylor Kelly Quek Alan Robertson Lorena Pantano Laura Mincarelli Luis N Sanchez Lisa Evers Jianmin Wu Mark Pinese Mark J Cowley Marc D Jones Emily K Colvin Adnan M Nagrial Emily S Humphrey Lorraine A Chantrill Amanda Mawson Jeremy Humphris Angela Chou Marina Pajic Christopher J Scarlett Andreia V Pinho Marc Giry-Laterriere Ilse Rooman Jaswinder S Samra James G Kench Jessica A Lovell Neil D Merrett Christopher W Toon Krishna Epari Nam Q Nguyen Andrew Barbour Nikolajs Zeps Kim Moran-Jones Nigel B Jamieson Janet S Graham Fraser Duthie Karin Oien Jane Hair Robert Grützmann Anirban Maitra Christine A Iacobuzio-Donahue Christopher L Wolfgang Richard A Morgan Rita T Lawlor Vincenzo Corbo Claudio Bassi Borislav Rusev Paola Capelli Roberto Salvia Giampaolo Tortora Debabrata Mukhopadhyay Gloria M Petersen Donna M Munzy William E Fisher Saadia A Karim James R Eshleman Ralph H Hruban Christian Pilarsky Jennifer P Morton Owen J Sansom Aldo Scarpa Elizabeth A Musgrove Ulla-Maja Hagbo Bailey Oliver Hofmann Robert L Sutherland David A Wheeler Anthony J Gill Richard A Gibbs John V Pearson Nicola Waddell Andrew V Biankin Sean M Grimmond

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

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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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016
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