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Nature. 2012 Nov 15;491(7424):399-405. doi: 10.1038/nature11547. Epub 2012 Oct 24.

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Collaborators (137)

Biankin AV, Johns AL, Mawson A, Chang DK, Scarlett CJ, Brancato MA, Rowe SJ, Simpson SL, Martyn-Smith M, Thomas MT, Chantrill LA, Chin VT, Chou A, Cowley MJ, Humphris JL, Jones MD, Mead R, Nagrial AM, Pajic M, Pettit J, Pinese M, Rooman I, Wu J, Tao J, DiPietro R, Watson C, Wong R, Pinho AV, Giry-Laterriere M, Daly RJ, Musgrove EA, Sutherland RL, Grimmond SM, Waddell N, Kassahn KS, Miller DK, Wilson PJ, Patch AM, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink J, Christ A, Bruxner T, Cloonan N, Newell F, Pearson JV, Samra JS, Gill AJ, Pavlakis N, Guminski A, Toon C, Biankin AV, Asghari R, Merrett ND, Chang DK, Pavey DA, Das A, Cosman PH, Ismail K, O'Connor C, Lam VW, McLeod D, Pleass HC, Richardson A, James V, Kench JG, Cooper CL, Joseph D, Sandroussi C, Crawford M, Gallagher J, Texler M, Forrest C, Laycock A, Epari KP, Ballal M, Fletcher DR, Mukhedkar S, Spry NA, DeBoer B, Chai M, Zeps N, Beilin M, Feeney K, Nguyen NQ, Ruszkiewicz AR, Worthley C, Tan CP, Debrencini T, Chen J, Brooke-Smith ME, Papangelis V, Tang H, Barbour AP, Clouston AD, Martin P, O'Rourke TJ, Chiang A, Fawcett JW, Slater K, Yeung S, Hatzifotis M, Hodgkinson P, Christophi C, Nikfarjam M, Mountain A, Eshleman JR, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Hodgin MB, Scarpa A, Lawlor RT, Capelli P, Beghelli S, Corbo V, Scardoni M, Pederzoli P, Tortora G, Bassi C, Tempero MA.

Author information

1
The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

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.

Comment in

PMID:
23103869
PMCID:
PMC3530898
DOI:
10.1038/nature11547
[Indexed for MEDLINE]
Free PMC Article

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