Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

A.V. Biankin, N. Waddell, K.S. Kassahn, M.-C. Gingras, L.B. Muthuswamy, A.L. Johns, D.K. Miller, P.J. Wilson, A.-M. Patch, J. Wu, D.K. Chang, M.J. Cowley, B.B. Gardiner, S. Song, I. Harliwong, S. Idrisoglu, C. Nourse, E. Nourbakhsh, S. Manning, S. WaniM. Gongora, M. Pajic, C.J. Scarlett, A.J. Gill, A.V. Pinho, I. Rooman, M. Anderson, O. Holmes, C. Leonard, D. Taylor, S. Wood, Q. Xu, K. Nones, J.L. Fink, A. Christ, T. Bruxner, N. Cloonan, G. Kolle, F. Newell, M. Pinese, R.S. Mead, J.L. Humphris, W. Kaplan, M.D. Jones, E.K. Colvin, A.M. Nagrial, E.S. Humphrey, A. Chou, V.T. Chin, L.A. Chantrill, A. Mawson, J.S. Samra, J.G. Kench, J.A. Lovell, R.J. Daly, N.D. Merrett, C. Toon, K. Epari, N.Q. Nguyen, A. Barbour, Nikolajs Zeps, N. Kakkar, F. Zhao, Y.Q. Wu, M. Wang, D.M. Muzny, W.E. Fisher, F.C. Brunicardi, S.E. Hodges, J.G. Reid, J. Drummond, K. Chang, Y. Han, L.R. Lewis, H. Dinh, C.J. Buhay, T. Beck, L. Timms, M. Sam, K. Begley, A. Brown, D. Pai, A. Panchal, N. Buchner, R. De Borja, R.E. Denroche, C.K. Yung, S. Serra, N. Onetto, D. Mukhopadhyay, M.-S. Tsao, P.A. Shaw, G.M. Petersen, S. Gallinger, R.H. Hruban, A. Maitra, C.A. Iacobuzio-Donahue, R.D. Schulick, C.L. Wolfgang, R.A. Morgan, R.T. Lawlor, P. Capelli, V. Corbo, M. Scardoni, G. Tortora, M.A. Tempero, K.M. Mann, N.A. Jenkins, P.A. Perez-Mancera, D.J. Adams, D.A. Largaespada, L.F.A. Wessels, A.G. Rust, L.D. Stein, D.A. Tuveson, N.G. Copeland, E.A. Musgrove, A. Scarpa, J.R. Eshleman, T.J. Hudson, R.L. Sutherland, D.A. Wheeler, J.V. Pearson, J.D. Mcpherson, R.A. Gibbs, S.M. Grimmond

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    1662 Citations (Scopus)

    Abstract

    Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
    Original languageEnglish
    Pages (from-to)399-405
    JournalNature
    Volume491
    Issue number7424
    Early online date24 Oct 2012
    DOIs
    Publication statusPublished - 15 Nov 2012

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