Journal Article

Genomic analyses identify molecular subtypes of pancreatic cancer

Leonard, Conrad, Kazakoff, Stephen, Anderson, Matthew J., Jamieson, Nigel B., Karim, Saadia A., Scarlett, Christopher J., Musgrove, Elizabeth A., Nagrial, Adnan M., Salvia, Roberto, Chou, Angela, Bailey, Ulla-Maja Hagbo, Murtaugh, L. Charles, Pinese, Mark, Wolfgang, Christopher L., Gibbs, Richard A., Morgan, Richard A., Nourbakhsh, Ehsan, Christ, Angelika N., Kassahn, Karin S., Quinn, Michael C., Sansom, Owen J., Duthie, Fraser, Capelli, Paola, Hair, Jane, Wheeler, David A., Wani, Shivangi, Hruban, Ralph H., Sanchez, Luis N., Toon, Christopher W., Munzy, Donna M., Bailey, Peter, Scarpa, Aldo, Pajic, Marina, Lovell, Jessica A., Lawlor, Rita T., Tortora, Giampaolo, Harliwong, Ivon, Mukhopadhyay, Debabrata, Pantano, Lorena, Biankin, Andrew V., Newell, Felicity, Grützmann, Robert, Bruxner, Tim J. C., Pinho, Andreia V., Gill, Anthony J., Taylor, Darrin, Evers, Lisa, Patch, Ann-Marie, Wood, Scott, Gingras, Marie-Claude, Mincarelli, Laura, Miller, David K., Oien, Karin, Holmes, Oliver, Cowley, Mark J., Colvin, Emily K., Iacobuzio-Donahue, Christine A., Petersen, Gloria M., Bassi, Claudio, Sutherland, Robert

2016

Overview

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. An integrated genomic analysis of 456 human pancreatic ductal adenocarcinomas identifies four subtypes defined by transcriptional expression profiles and show that these are associated with distinct histopathological characteristics and differential prognosis. Pancreatic cancer genomics Sean Grimmond and colleagues report integrated genomic analysis of 456 pancreatic ductal adenocarcinomas. They identify four subtypes defined by expression profiles, characterize their transcriptional networks, and show that these are associated with distinct histopathological characteristics and differential survival.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/69 / 692/699/67/1504/1713 / Animals / Basic Helix-Loop-Helix Transcription Factors - genetics / Carcinoma, Pancreatic Ductal - classification / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - immunology / Carcinoma, Pancreatic Ductal - metabolism / Carcinoma, Pancreatic Ductal - pathology / Cell Line, Tumor / DNA Methylation / DNA-Binding Proteins - genetics / Gene expression / Gene Expression Regulation, Neoplastic / Gene Regulatory Networks / Genes / Genes, Neoplasm - genetics / Genome, Human - genetics / Genomes / Genomics / Hepatocyte Nuclear Factor 3-beta - genetics / Hepatocyte Nuclear Factor 3-gamma - genetics / Histone Demethylases - genetics / Homeobox Protein Nkx-2.2 / Homeodomain Proteins - genetics / Humanities and Social Sciences / Humans / Methods / Mice / multidisciplinary / Mutation / Mutation - genetics / Nuclear Proteins - genetics / Pancreatic cancer / Pancreatic Neoplasms - classification / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - immunology / Pancreatic Neoplasms - metabolism / Pancreatic Neoplasms - pathology / Physiological aspects / Prognosis / Receptors, Cytoplasmic and Nuclear - genetics / Science / Survival Analysis / Trans-Activators - genetics / Transcription Factors - genetics / Transcription, Genetic / Transcriptome / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Proteins - genetics / Tumors / Zebrafish Proteins