Genomic analyses identify molecular subtypes of pancreatic cancer

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 & 83 others 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, Australian Pancreatic Cancer Genome Initiative

*Corresponding author for this work

Research output: Contribution to journalArticle

1104 Citations (Scopus)

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 TP63ΔN 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.

Original languageEnglish
Pages (from-to)47-52
Number of pages6
JournalNature
Volume531
Issue number7592
DOIs
Publication statusPublished - 3 Mar 2016
Externally publishedYes

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