Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Biankin, Andrew V., Waddell, Nicola, Kassahn, Karin S., Gingras, Marie-Claude, Muthuswamy, Lakshmi B., Johns, Amber L., Miller, David K., Wilson, Peter J., Patch, Ann-Marie, Wu, Jianmin, Chang, David K., Cowley, Mark J., Gardiner, Brooke B., Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Pajic, Marina, Scarlett, Christopher J., Gill, Anthony J., Pinho, Andreia V., Rooman, Ilse, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Christina, Nones, Katia, Fink, J. Lynn, Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Kolle, Gabriel, Newell, Felicity, Pinese, Mark, Mead, R. Scott, Humphris, Jeremy L., Kaplan, Warren, Jones, Marc D., Colvin, Emily K., Nagrial, Adnan M., Humphrey, Emily S., Chou, Angela, Chin, Venessa T., Chantrill, Lorraine A., Mawson, Amanda, Samra, Jaswinder S., Kench, James G., Lovell, Jessica A., Daly, Roger J., Merrett, Neil D., Toon, Christopher, Epari, Krishna, Nguyen, Nam Q., Barbour, Andrew, Zeps, Nikolajs, Australian Pancreatic Cancer Genome Initiative, Pearson, John V. and Grimmond, Sean M. (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491 7424: 399-405. doi:10.1038/nature11547

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Author Biankin, Andrew V.
Waddell, Nicola
Kassahn, Karin S.
Gingras, Marie-Claude
Muthuswamy, Lakshmi B.
Johns, Amber L.
Miller, David K.
Wilson, Peter J.
Patch, Ann-Marie
Wu, Jianmin
Chang, David K.
Cowley, Mark J.
Gardiner, Brooke B.
Song, Sarah
Harliwong, Ivon
Idrisoglu, Senel
Nourse, Craig
Nourbakhsh, Ehsan
Manning, Suzanne
Wani, Shivangi
Gongora, Milena
Pajic, Marina
Scarlett, Christopher J.
Gill, Anthony J.
Pinho, Andreia V.
Rooman, Ilse
Anderson, Matthew
Holmes, Oliver
Leonard, Conrad
Taylor, Darrin
Wood, Scott
Xu, Christina
Nones, Katia
Fink, J. Lynn
Christ, Angelika
Bruxner, Tim
Cloonan, Nicole
Kolle, Gabriel
Newell, Felicity
Pinese, Mark
Mead, R. Scott
Humphris, Jeremy L.
Kaplan, Warren
Jones, Marc D.
Colvin, Emily K.
Nagrial, Adnan M.
Humphrey, Emily S.
Chou, Angela
Chin, Venessa T.
Chantrill, Lorraine A.
Mawson, Amanda
Samra, Jaswinder S.
Kench, James G.
Lovell, Jessica A.
Daly, Roger J.
Merrett, Neil D.
Toon, Christopher
Epari, Krishna
Nguyen, Nam Q.
Barbour, Andrew
Zeps, Nikolajs
Australian Pancreatic Cancer Genome Initiative
Pearson, John V.
Grimmond, Sean M.
Title Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Journal name Nature   Check publisher's open access policy
ISSN 0028-0836
Publication date 2012-11-01
Sub-type Article (original research)
DOI 10.1038/nature11547
Open Access Status File (Author Post-print)
Volume 491
Issue 7424
Start page 399
End page 405
Total pages 7
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Keyword Ductal adenocarcinoma
Somatic mutations
Invasive growth
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 24 October 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
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Citation counts: TR Web of Science Citation Count  Cited 652 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 692 times in Scopus Article | Citations
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Created: Tue, 30 Oct 2012, 02:20:23 EST by Dr Sarah Song on behalf of Institute for Molecular Bioscience