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 ChinMatthew 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, Ilse Rooman, Australian Pancreatic Cancer Genome Initiative

Onderzoeksoutput: Articlepeer review

2157 Citaten (Scopus)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)47-52
Aantal pagina's6
TijdschriftNature
Volume531
Nummer van het tijdschrift7592
DOI's
StatusPublished - 2016

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