Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes - PubMed (original) (raw)

. 2012 Nov 15;491(7424):399-405.

doi: 10.1038/nature11547. Epub 2012 Oct 24.

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; Australian Pancreatic Cancer Genome Initiative; 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

Collaborators, Affiliations

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Andrew V Biankin et al. Nature. 2012.

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.

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Figures

Figure 1

Figure 1. Mutations and copy number variation in axon guidance genes

Axon guidance pathway genes with recurrent mutations and/or copy-number changes defined by GISTIC2.0 analysis (Q < 0.2), and manually reviewed for focal alterations. a, SNV and CNV frequency per patient with gene-centric summary (left) and patient-centric summary (top); numbers of patients with mutations and proportion of each event are presented. Please see Supplementary Table 4 for further details. b, Clinico-pathological variables for individual patients. APGI, Australian Pancreatic Cancer Genome Initiative; BCM, Baylor College of Medicine; IPMN, intraductal papillary mucinous neoplasm; Mod, moderately differentiated; OICR, Ontario Institute for Cancer Research; PDAC, pancreatic ductal adenocarcinoma; Undiff, undifferentiated.

Figure 2

Figure 2. SLIT/ROBO signalling in pancreatic ductal adenocarcinoma

a, SLIT/ROBO signalling normally enhances β-catenin complex formation with E-cadherin and suppresses WNT signalling activity. Loss of ROBO1/2 signalling promotes stabilization of β-catenin, which decreases E-cadherin complex formation and cell adhesion and augments WNT signalling activity through increased nuclear translocation of β-catenin. In addition, SLIT/ROBO signalling can downregulate MET signalling activity; loss of ROBO signalling activity promotes MET signalling downstream and may have an impact on therapeutic strategies aimed at inhibiting MET activity at the receptor level. (Adapted from ref. .) Aberrations in SLIT2 and/or ROBO1/2 affected 23% of patients (6% mutated with 1 patient showing mutations in both SLIT2 and ROBO2), with 18% demonstrating CNV corresponding to loss of the gene. b, c, High expression of SLIT receptor ROBO2 was associated with a better prognosis (b), and high expression of ROBO3, an inhibitor of ROBO2, showed an inverse relationship, with high levels associated with poor survival (c). HR, hazard ratio.

Figure 3

Figure 3. Axon guidance genes in human and murine pancreatic ductal adenocarcinoma

a, Kaplan–Meier survival curves showing co-segregation of aberrant expression of components of semaphorin signalling with outcome. Amplification at SEMA3A and PLXNA1 loci was associated with high mRNA expression and both are independent poor prognostic factors. b, Quantitative RT–PCR for components of semaphorin and SLIT/ROBO signalling in murine models of early (acinar-to-ductal metaplasia (ADM) and pancreatic injury) and established PDAC in genetically engineered mice with a _Pdx1_-promoter-driven activating mutation of Kras and mutant Tp53 allele (Pdx1-Cre; LSL-KrasG12D; LSL-Trp53R172H). Error bars represent standard error of the mean (see Supplementary Table 15 for details).

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