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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

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.

SUBMITTER: Biankin AV

PROVIDER: S-EPMC3530898 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Biankin Andrew V AV Waddell Nicola N Kassahn Karin S KS Gingras Marie-Claude MC Muthuswamy Lakshmi B LB Johns Amber L AL Miller David K DK Wilson Peter J PJ Patch Ann-Marie AM Wu Jianmin J Chang David K DK Cowley Mark J MJ Gardiner Brooke B BB Song Sarah S Harliwong Ivon I Idrisoglu Senel S Nourse Craig C Nourbakhsh Ehsan E Manning Suzanne S Wani Shivangi S Gongora Milena M Pajic Marina M Scarlett Christopher J CJ Gill Anthony J AJ Pinho Andreia V AV Rooman Ilse I Anderson Matthew M Holmes Oliver O Leonard Conrad C Taylor Darrin D Wood Scott S Xu Qinying Q Nones Katia K Fink J Lynn JL Christ Angelika A Bruxner Tim T Cloonan Nicole N Kolle Gabriel G Newell Felicity F Pinese Mark M Mead R Scott RS Humphris Jeremy L JL Kaplan Warren W Jones Marc D MD Colvin Emily K EK Nagrial Adnan M AM Humphrey Emily S ES Chou Angela A Chin Venessa T VT Chantrill Lorraine A LA Mawson Amanda A Samra Jaswinder S JS Kench James G JG Lovell Jessica A JA Daly Roger J RJ Merrett Neil D ND Toon Christopher C Epari Krishna K Nguyen Nam Q NQ Barbour Andrew A Zeps Nikolajs N Kakkar Nipun N Zhao Fengmei F Wu Yuan Qing YQ Wang Min M Muzny Donna M DM Fisher William E WE Brunicardi F Charles FC Hodges Sally E SE Reid Jeffrey G JG Drummond Jennifer J Chang Kyle K Han Yi Y Lewis Lora R LR Dinh Huyen H Buhay Christian J CJ Beck Timothy T Timms Lee L Sam Michelle M Begley Kimberly K Brown Andrew A Pai Deepa D Panchal Ami A Buchner Nicholas N De Borja Richard R Denroche Robert E RE Yung Christina K CK Serra Stefano S Onetto Nicole N Mukhopadhyay Debabrata D Tsao Ming-Sound MS Shaw Patricia A PA Petersen Gloria M GM Gallinger Steven S Hruban Ralph H RH Maitra Anirban A Iacobuzio-Donahue Christine A CA Schulick Richard D RD Wolfgang Christopher L CL Morgan Richard A RA Lawlor Rita T RT Capelli Paola P Corbo Vincenzo V Scardoni Maria M Tortora Giampaolo G Tempero Margaret A MA Mann Karen M KM Jenkins Nancy A NA Perez-Mancera Pedro A PA Adams David J DJ Largaespada David A DA Wessels Lodewyk F A LF Rust Alistair G AG Stein Lincoln D LD Tuveson David A DA Copeland Neal G NG Musgrove Elizabeth A EA Scarpa Aldo A Eshleman James R JR Hudson Thomas J TJ Sutherland Robert L RL Wheeler David A DA Pearson John V JV McPherson John D JD Gibbs Richard A RA Grimmond Sean M SM

Nature 20121024 7424

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 mutation ...[more]

PMID: 23103869

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Project description:During the development of the Drosophila central nervous system the process of midline crossing is orchestrated by a number of guidance receptors and ligands. Many key axon guidance molecules have been identified in both invertebrates and vertebrates, but the transcriptional regulation of growth cone guidance remains largely unknown. One open question is whether transcriptional regulation plays a role in midline crossing, or if local translation can account for the necessary fine tuning of protein levels. To investigate this issue, we conducted a genome wide analysis of transcription in Drosophila embryos using wild type and a number of well-characterized Drosophila guidance mutants and transgenics. We also analyzed a publicly available microarray time course of Drosophila embryonic development with an axon guidance focus. Using hopach, a novel clustering method which is well suited to microarray data analysis, we identified groups of genes with similar expression patterns across guidance mutants and transgenics. We then systematically characterized the resulting clusters with respect to their relevance to axon guidance using two complementary controlled vocabularies: the Gene Ontology (GO) and anatomical annotations of the Atlas of Pattern of Gene Expression (APoGE) in situ hybridization database. The analysis indicates that regulation of gene expression does play a role in the process of axon guidance in Drosophila. We also find a strong link between axon guidance and hemocyte migration, a result that agrees with mounting evidence that axon guidance molecules are co-opted in vertebrate vascularization. Cell cyclin activity in the context of axon guidance is also suggested from our array data. RNA and protein patterns of cell cyclin in axon guidance mutants and transgenics support this possible link. This study provides important insights into the regulation of axon guidance in vivo and suggests that transcription does play a role in control of axon guidance. Keywords: Mutant Analysis

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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Publications

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

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