Journal Article

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Leonard, Conrad, Christ, Angelika, Kolle, Gabriel, Muzny, Donna M., Scarlett, Christopher J., Muthuswamy, Lakshmi B., Musgrove, Elizabeth A., Nagrial, Adnan M., Yung, Christina K., Chou, Angela, De Borja, Richard, Tsao, Ming-Sound, Pinese, Mark, Wolfgang, Christopher L., Gibbs, Richard A., Morgan, Richard A., Nourbakhsh, Ehsan, Kassahn, Karin S., Brown, Andrew, Sam, Michelle, Reid, Jeffrey G., Toon, Christopher, Capelli, Paola, Wheeler, David A., Wang, Min, Wani, Shivangi, Buhay, Christian J., Pai, Deepa, Buchner, Nicholas, Bruxner, Tim, Stein, Lincoln D., McPherson, John D., Tempero, Margaret A., Chin, Venessa T., Lewis, Lora R., Hruban, Ralph H., Timms, Lee, Scarpa, Aldo, Pajic, Marina, Lovell, Jessica A., Gallinger, Steven, Beck, Timothy, Lawlor, Rita T., Tortora, Giampaolo, Adams, David J., Harliwong, Ivon, Mukhopadhyay, Debabrata, Denroche, Robert E., Onetto, Nicole, Scardoni, Maria, Kaplan, Warren, Biankin, Andrew V., Newell, Felicity, Tuveson, David A., Gill, Anthony J., Pinho, Andreia V., Taylor, Darrin, Patch, Ann-Marie, Wood, Scott, Gingras, Marie-Claude, Miller, David K., Drummond, Jennifer, Cowl

2012

Overview

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. Exome sequencing and copy number analysis are used to define genomic aberrations in early sporadic pancreatic ductal adenocarcinoma; among the findings are mutations in genes involved in chromatin modification and DNA damage repair, and frequent and diverse somatic aberrations in genes known as embryonic regulators of axon guidance. New mutations identified in pancreatic cancer This large-scale study presents exome sequencing and copy number variant analysis from 142 patients with pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer. Among the findings are mutations in genes involved in chromatin modification and DNA damage repair, not previously implicated in this disease. Importantly, the data show that abnormal expression of genes involved in slit and semaphorin signalling is associated with poor patient survival, and in animal models was associated with disease development and progression.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/69 / 631/80/86 / 692/699/67/1504/1713 / Animals / Axons / Axons - metabolism / Biological and medical sciences / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - pathology / Gastroenterology. Liver. Pancreas. Abdomen / Gene Dosage / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Genome - genetics / Health aspects / Humanities and Social Sciences / Humans / Kaplan-Meier Estimate / Liver. Biliary tract. Portal circulation. Exocrine pancreas / Medical sciences / Mice / multidisciplinary / Mutation / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - pathology / Proteins - genetics / Science / Signal Transduction / Tumors