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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Open accessAbstract
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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“Among the identified genomic alterations (GAs) in PDAC, oncogenic KRAS mutations are the most common, occurring in close to 90% of patients, followed by TP53, CDKN2A, and SMAD47,8.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [7]
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“Amongst these are four canonical mutations – KRAS (~85%), TP53 (60–70%), CDKN2A (>50%), and SMAD4 (~50%).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [50]
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Metadata
- Authors
- Initiative, A. P. C. G., Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M.-C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A.-M., Wu, J., Chang, D. K., Cowley, M. J., Gardiner, B. B., Song, S., Harliwong, I., Idrisoglu, S., Nourse, C., Nourbakhsh, E., Manning, S., Wani, S., Gongora, M., Pajic, M., Scarlett, C. J., Gill, A. J., Pinho, A. V., Rooman, I., Anderson, M., Holmes, O., Leonard, C., Taylor, D., Wood, S., Xu, Q., Nones, K., Lynn Fink, J., Christ, A., Bruxner, T., Cloonan, N., Kolle, G., Newell, F., Pinese, M., Scott Mead, R., Humphris, J. L., Kaplan, W., Jones, M. D., Colvin, E. K., Nagrial, A. M., Humphrey, E. S., Chou, A., Chin, V. T., Chantrill, L. A., Mawson, A., Samra, J. S., Kench, J. G., Lovell, J. A., Daly, R. J., Merrett, N. D., Toon, C., Epari, K., Nguyen, N. Q., Barbour, A., Zeps, N., Kakkar, N., Zhao, F., Qing Wu, Y., Wang, M., Muzny, D. M., Fisher, W. E., Charles Brunicardi, F., Hodges, S. E., Reid, J. G., Drummond, J., Chang, K., Han, Y., Lewis, L. R., Dinh, H., Buhay, C. J., Beck, T., Timms, L., Sam, M., Begley, K., Brown, A., Pai, D., Panchal, A., Buchner, N., De Borja, R., Denroche, R. E., Yung, C. K., Serra, S., Onetto, N., Mukhopadhyay, D., Tsao, M.-S., Shaw, P. A., Petersen, G. M., Gallinger, S., Hruban, R. H., Maitra, A., Iacobuzio-Donahue, C. A., Schulick, R. D., Wolfgang, C. L., Morgan, R. A., Lawlor, R. T., Capelli, P., Corbo, V., Scardoni, M., Tortora, G., Tempero, M. A., Mann, K. M., Jenkins, N. A., Perez-Mancera, P. A., Adams, D. J., Largaespada, D. A., Wessels, L. F. A., Rust, A. G., Stein, L. D., Tuveson, D. A., Copeland, N. G., Musgrove, E. A., Scarpa, A., Eshleman, J. R., Hudson, T. J., Sutherland, R. L., Wheeler, D. A., Pearson, J. V., McPherson, J. D., Gibbs, R. A., & Grimmond, S. M.
- Affiliations
- Garvan Institute of Medical Research (AU)
- The University of Queensland (AU)
- Ontario Institute for Cancer Research (CA)
- The University of Sydney (AU)
- Royal Adelaide Hospital (AU)
- St John of God Subiaco Hospital (AU)
- Baylor College of Medicine (US)
- University of California, Los Angeles (US)
- University Health Network (CA)
- Johns Hopkins University (US)
- University of Verona (IT)
- Houston Methodist (US)
- University of Minnesota (US)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Grimmond, Sean M.
- ORCID
- Biankin, Andrew V.
- Waddell, Nicola
- Kassahn, Karin S.
- Gingras, Marie-Claude
- Muthuswamy, Lakshmi B.
- Johns, Amber L.
- Wilson, Peter J.
- Patch, Ann-Marie
- Wu, Jianmin
- Chang, David K.
- Cowley, Mark J.
- Gardiner, Brooke B.
- Song, Sarah
- Harliwong, Ivon
- Nourbakhsh, Ehsan
- Manning, Suzanne
- Wani, Shivangi
- Pajic, Marina
- Scarlett, Christopher J.
- Gill, Anthony J.
- Pinho, Andreia V.
- Rooman, Ilse
- Anderson, Matthew
- Holmes, Oliver
- Leonard, Conrad
- Wood, Scott
- Christ, Angelika
- Cloonan, Nicole
- Newell, Felicity
- Pinese, Mark
- Kaplan, Warren
- Jones, Marc D.
- Colvin, Emily K.
- Nagrial, Adnan M.
- Chou, Angela
- Chin, Venessa T.
- Chantrill, Lorraine A.
- Mawson, Amanda
- Samra, Jaswinder S.
- Kench, James G.
- Daly, Roger J.
- Merrett, Neil D.
- Toon, Christopher
- Nguyen, Nam Q.
- Barbour, Andrew
- Zeps, Nikolajs
- Zhao, Fengmei
- Muzny, Donna M.
- Drummond, Jennifer
- Chang, Kyle
- Han, Yi
- Dinh, Huyen
- Beck, Timothy
- Begley, Kimberly
- Brown, Andrew
- Denroche, Robert E.
- Yung, Christina K.
- Serra, Stefano
- Mukhopadhyay, Debabrata
- Tsao, Ming-Sound
- Petersen, Gloria M.
- Hruban, Ralph H.
- Maitra, Anirban
- Schulick, Richard D.
- Wolfgang, Christopher L.
- Lawlor, Rita T.
- Corbo, Vincenzo
- Tortora, Giampaolo
- Tempero, Margaret A.
- Mann, Karen M.
- Jenkins, Nancy A.
- Adams, David J.
- Wessels, Lodewyk F. A.
- Rust, Alistair G.
- Stein, Lincoln D.
- Tuveson, David A.
- Scarpa, Aldo
- Eshleman, James R.
- Hudson, Thomas J.
- Wheeler, David A.
- Pearson, John V.
- McPherson, John D.
- Gibbs, Richard A.
- Grimmond, Sean M.
- Venue
- Nature
- Published
- 2012-10-24
- Volume
- 491
- Issue
- 7424
- Pages
- 399-405
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3530898
- OpenAlex
- W2161884651
- Cited by
- 2,058
- References
- 41
- Citations by year
- 2026: 62 · 2025: 98 · 2024: 90 · 2023: 128 · 2022: 173 · 2021: 190 · 2020: 168 · 2019: 163 · 2018: 159 · 2017: 187 · 2016: 191 · 2015: 176 · 2014: 157 · 2013: 113 · 2012: 1
- FWCI
- 70.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- American Association for Cancer Research
- Cancer Prevention and Research Institute of Texas (RP101353-P7, RP101353)
- Johns Hopkins University (P50CA062924)
- Royal College of Pathologists of Australasia
- Wellcome Trust
- Australian Government
- Cancer Research UK (13031)
- Australian Cancer Research Foundation
- Cancer Institute NSW
- Gastroenterological Society of Australia
- Royal Australasian College of Physicians
- Agency for Science, Technology and Research
- Petre Foundation
- Queensland Government
- R.T. Hall Trust
- Associazione Italiana per la Ricerca sul Cancro (12182, 5 x mille)
- Università degli Studi di Verona
- Ministero dello Sviluppo Economico
- National Institutes of Health (CA102701)
- Medical Research Council
- National Health and Medical Research Council (535914, 631701, 535903, 427601)
- Cancer Council NSW (SRP06-01)
- National Human Genome Research Institute (HG003273, U54HG003273)
- National Cancer Institute (CA102701, R01CA-97075, P01CA134292, P50CA101955, P50CA102701, R01CA113636, R01CA097075, P50CA062924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pancreatic ductal adenocarcinoma, axon guidance genes, somatic mutations, copy number variation, chromatin modification, DNA repair, ATM, carcinogenesis, pathway analysis, patient survival, Sleeping Beauty transposon mutagenesis, early-stage pancreatic cancer
- MeSH terms
- Animals, Axons, Humans, Mutation, Pancreatic Neoplasms, Proteins, Signal Transduction, Gene Expression Regulation, Neoplastic, Genome, Gene Dosage, Carcinoma, Pancreatic Ductal, Mice, Kaplan-Meier Estimate
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