Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Andrew V Biankin Nicola Waddell Karin S Kassahn Marie-Claude Gingras Lakshmi B Muthuswamy Amber L Johns David K Miller Peter J Wilson Ann-Marie Patch Jianmin Wu David K Chang Mark J Cowley Brooke B Gardiner Sarah Song Ivon Harliwong Senel Idrisoglu Craig Nourse Ehsan Nourbakhsh Suzanne Manning Shivangi Wani Milena Gongora Marina Pajic Christopher J Scarlett Anthony J Gill Andreia V Pinho Ilse Rooman Matthew Anderson Oliver Holmes Conrad Leonard Darrin Taylor Scott Wood Qinying Xu Katia Nones J Lynn Fink Angelika Christ Tim Bruxner Nicole Cloonan Gabriel Kolle Felicity Newell Mark Pinese R Scott Mead Jeremy L Humphris Warren Kaplan Marc D Jones Emily K Colvin Adnan M Nagrial Emily S Humphrey Angela Chou Venessa T Chin Lorraine A Chantrill Amanda Mawson Jaswinder S Samra James G Kench Jessica A Lovell Roger J Daly Neil D Merrett Christopher Toon Krishna Epari Nam Q Nguyen Andrew Barbour Nikolajs Zeps Nipun Kakkar Fengmei Zhao Yuan Qing Wu Min Wang Donna M Muzny William E Fisher F Charles Brunicardi Sally E Hodges Jeffrey G Reid Jennifer Drummond Kyle Chang Yi Han Lora R Lewis Huyen Dinh Christian J Buhay Timothy Beck Lee Timms Michelle Sam Kimberly Begley Andrew Brown Deepa Pai Ami Panchal Nicholas Buchner Richard De Borja Robert E Denroche Christina K Yung Stefano Serra Nicole Onetto Debabrata Mukhopadhyay Ming-Sound Tsao Patricia A Shaw Gloria M Petersen Steven Gallinger Ralph H Hruban Anirban Maitra Christine A Iacobuzio-Donahue Richard D Schulick Christopher L Wolfgang Richard A Morgan Rita T Lawlor Paola Capelli Vincenzo Corbo Maria Scardoni Giampaolo Tortora Margaret A Tempero Karen M Mann Nancy A Jenkins Pedro A Perez-Mancera David J Adams David A Largaespada Lodewyk F A Wessels Alistair G Rust Lincoln D Stein David A Tuveson Neal G Copeland Elizabeth A Musgrove Aldo Scarpa James R Eshleman Thomas J Hudson Robert L Sutherland David A Wheeler John V Pearson John D McPherson Richard A Gibbs Sean M Grimmond

Nature 2012 Nov 24;491(7424):399-405. Epub 2012 Oct 24.

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

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.

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