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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Biankin AV | Waddell N | Kassahn KS | Gingras MC | Muthuswamy LB | Johns AL | Miller DK | Wilson PJ | Patch AM | Wu J | Chang DK | Cowley MJ | Gardiner BB | Song S | Harliwong I | Idrisoglu S | Nourse C | Nourbakhsh E | Manning S | Wani S | Gongora M | Pajic M | Scarlett CJ | Gill AJ | Pinho AV | Rooman I | Anderson M | Holmes O | Leonard C | Taylor D | Wood S | Xu Q | Nones K | Fink JL | Christ A | Bruxner T | Cloonan N | Kolle G | Newell F | Pinese M | Mead RS | Humphris JL | Kaplan W | Jones MD | Colvin EK | Nagrial AM | Humphrey ES | Chou A | Chin VT | Chantrill LA | Mawson A | Samra JS | Kench JG | Lovell JA | Daly RJ | Merrett ND | Toon C | Epari K | Nguyen NQ | Barbour A | Zeps N | Australian Pancreatic Cancer Genome Initiative | Kakkar N | Zhao F | Wu YQ | Wang M | Muzny DM | Fisher WE | Brunicardi FC | Hodges SE | Reid JG | Drummond J | Chang K | Han Y | Lewis LR | Dinh H | Buhay CJ | Beck T | Timms L | Sam M | Begley K | Brown A | Pai D | Panchal A | Buchner N | De Borja R | Denroche RE | Yung CK | Serra S | Onetto N | Mukhopadhyay D | Tsao MS | Shaw PA | Petersen GM | Gallinger S | Hruban RH | Maitra A | Iacobuzio-Donahue CA | Schulick RD | Wolfgang CL | Morgan RA | Lawlor RT | Capelli P | Corbo V | Scardoni M | Tortora G | Tempero MA | Mann KM | Jenkins NA | Perez-Mancera PA | Adams DJ | Largaespada DA | Wessels LF | Rust AG | Stein LD | Tuveson DA | Copeland NG | Musgrove EA | Scarpa A | Eshleman JR | Hudson TJ | Sutherland RL | Wheeler DA | Pearson JV | McPherson JD | Gibbs RA | Grimmond SM
Nature | Nov 15, 2012

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.

Pubmed ID: 23103869 RIS Download

Mesh terms: Animals | Axons | Carcinoma, Pancreatic Ductal | Gene Dosage | Gene Expression Regulation, Neoplastic | Genome | Humans | Kaplan-Meier Estimate | Mice | Mutation | Pancreatic Neoplasms | Proteins | Signal Transduction

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Associated grants

  • Agency: NCI NIH HHS, Id: P50 CA062924
  • Agency: NCI NIH HHS, Id: P01 CA134292
  • Agency: NHGRI NIH HHS, Id: U54 HG003273
  • Agency: NCI NIH HHS, Id: P50 CA101955
  • Agency: NCI NIH HHS, Id: P50 CA102701
  • Agency: Cancer Research UK, Id: 13031
  • Agency: Cancer Research UK, Id: P50CA062924
  • Agency: NCI NIH HHS, Id: R01 CA97075
  • Agency: NCI NIH HHS, Id: R01 CA097075
  • Agency: NCI NIH HHS, Id: 2P50CA101955
  • Agency: Wellcome Trust, Id: P01CA134292
  • Agency: NCI NIH HHS, Id:
  • Agency: NCI NIH HHS, Id:

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