Genomic analyses identify molecular subtypes of pancreatic cancer.

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.

• 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, Australian Pancreatic Cancer Genome Initiative, 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
• Journal: Nature (Nature) Vol. 531 Issue 7592 Pg. 47-52 (Mar 03 2016) ISSN: 1476-4687 [Electronic] England
• PMID: 26909576 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• DNA-Binding Proteins
• FOXA2 protein, human
• FOXA3 protein, human
• Homeobox Protein Nkx-2.2
• Homeodomain Proteins
• MNX1 protein, human
• NEUROD1 protein, human
• NKX2-2 protein, human
• NR5A2 protein, human
• Nkx2-2 protein, mouse
• Nuclear Proteins
• RBPJL protein, human
• Receptors, Cytoplasmic and Nuclear
• TP53 protein, human
• TP63 protein, human
• Trans-Activators
• Transcription Factors
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• Zebrafish Proteins
• nkx2.2b protein, zebrafish
• pancreatic and duodenal homeobox 1 protein
• Hepatocyte Nuclear Factor 3-gamma
• Hepatocyte Nuclear Factor 3-beta
• Histone Demethylases
• KDM6A protein, human

Topics

• Animals
• Basic Helix-Loop-Helix Transcription Factors (genetics)
• Carcinoma, Pancreatic Ductal (classification, genetics, immunology, metabolism, pathology)
• Cell Line, Tumor
• DNA Methylation
• DNA-Binding Proteins (genetics)
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Genes, Neoplasm (genetics)
• Genome, Human (genetics)
• Genomics
• 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
• Mutation (genetics)
• Nuclear Proteins (genetics)
• Pancreatic Neoplasms (classification, genetics, immunology, metabolism, 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