Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

TitlePancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Publication TypeJournal Article
Year of Publication2012
AuthorsBiankin, AV, Waddell, N, Kassahn, KS, Gingras, M-C, Muthuswamy, LB, Johns, AL, Miller, DK, Wilson, PJ, Patch, A-M, Wu, J, Chang, DK, Cowley, MJ, Gardiner, BB, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Pajic, M, Scarlett, CJ, Gill, AJ, Pinho, AV, Rooman, I, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, Q, Nones, K, J Fink, L, Christ, A, Bruxner, T, Cloonan, N, Kolle, G, Newell, F, Pinese, M, R Mead, S, Humphris, JL, Kaplan, W, Jones, MD, Colvin, EK, Nagrial, AM, Humphrey, ES, Chou, A, Chin, VT, Chantrill, LA, Mawson, A, Samra, JS, Kench, JG, Lovell, JA, Daly, RJ, Merrett, ND, Toon, C, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Kakkar, N, Zhao, F, Wu, YQing, Wang, M, Muzny, DM, Fisher, WE, F Brunicardi, C, Hodges, SE, Reid, JG, Drummond, JA, Chang, K, Han, Y, Lewis, LR, Dinh, H, Buhay, CJ, Beck, T, Timms, L, Sam, M, Begley, K, Brown, A, Pai, D, Panchal, A, Buchner, N, De Borja, R, Denroche, RE, Yung, CK, Serra, S, Onetto, N, Mukhopadhyay, D, Tsao, M-S, Shaw, PA, Petersen, GM, Gallinger, S, Hruban, RH, Maitra, A, Iacobuzio-Donahue, CA, Schulick, RD, Wolfgang, CL, Morgan, RA, Lawlor, RT, Capelli, P, Corbo, V, Scardoni, M, Tortora, G, Tempero, MA, Mann, KM, Jenkins, NA, Perez-Mancera, PA, Adams, DJ, Largaespada, DA, Wessels, LFA, Rust, AG, Stein, LD, Tuveson, DA, Copeland, NG, Musgrove, EA, Scarpa, A, Eshleman, JR, Hudson, TJ, Sutherland, RL, Wheeler, DA, Pearson, JV, McPherson, JD, Gibbs, RA, Grimmond, SM
Corporate AuthorsAustralian Pancreatic Cancer Genome Initiative
JournalNature
Volume491
Issue7424
Pagination399-405
Date Published2012 Nov 15
ISSN1476-4687
KeywordsAnimals, Axons, Carcinoma, Pancreatic Ductal, Gene Dosage, Gene Expression Regulation, Neoplastic, Genome, Humans, Kaplan-Meier Estimate, Mice, Mutation, Pancreatic Neoplasms, Proteins, Signal Transduction
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.

DOI10.1038/nature11547
Alternate JournalNature
PubMed ID23103869
PubMed Central IDPMC3530898
Grant List13031 / / Cancer Research UK / United Kingdom
2P50CA101955 / CA / NCI NIH HHS / United States
P01CA134292 / CA / NCI NIH HHS / United States
P50 CA101955 / CA / NCI NIH HHS / United States
P50 CA102701 / CA / NCI NIH HHS / United States
P50 CA102701 / CA / NCI NIH HHS / United States
P50CA062924 / CA / NCI NIH HHS / United States
R01 CA097075 / CA / NCI NIH HHS / United States
R01 CA97075 / CA / NCI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG003273 / HG / NHGRI NIH HHS / United States
/ / Cancer Research UK / United Kingdom
/ / Wellcome Trust / United Kingdom