Genomic analyses identify molecular subtypes of pancreatic cancer

P. Bailey, D.K. Chang, K. Nones, A.L. Johns, A.M. Patch, M.C. Gingras, D.K. Miller, A.N. Christ, T.J.C. Bruxner, M.C. Quinn, C. Nourse, L.C. Murtaugh, I. Harliwong, S. Idrisoglu, S. Manning, E. Nourbakhsh, S. Wani, L. Fink, O. Holmes, V. ChinM.J. Anderson, S. Kazakoff, C. Leonard, F. Newell, N. Waddell, S. Wood, Q. Xu, P.J. Wilson, N. Cloonan, K.S. Kassahn, D. Taylor, K. Quek, A. Robertson, L. Pantano, L. Mincarelli, L.N. Sanchez, L. Evers, J. Wu, M. Pinese, M.J. Cowley, M.D. Jones, E.K. Colvin, A.M. Nagrial, E.S. Humphrey, L.A. Chantrill, A. Mawson, J. Humphris, A. Chou, M. Pajic, C.J. Scarlett, A.V. Pinho, M. Giry-Laterriere, I. Rooman, J.S. Samra, Nikolajs Zeps

    Research output: Contribution to journalArticle

    1113 Citations (Scopus)

    Abstract

    © 2016 Macmillan Publishers Limited. All rights reserved. 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
    Early online date24 Feb 2016
    DOIs
    Publication statusPublished - 3 Mar 2016

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