Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation

Marie Claude Gingras, Kyle R. Covington, David K. Chang, Lawrence A. Donehower, Anthony J. Gill, Michael M. Ittmann, Chad J. Creighton, Amber L. Johns, Eve Shinbrot, Ninad Dewal, William E. Fisher, Christian Pilarsky, Robert Grützmann, Michael J. Overman, Nigel B. Jamieson, George Van Buren, Jennifer Drummond, Kimberly Walker, Oliver A. Hampton, Liu XiDonna M. Muzny, Harsha Doddapaneni, Sandra L. Lee, Michelle Bellair, Jianhong Hu, Yi Han, Huyen H. Dinh, Mike Dahdouli, Jaswinder S. Samra, Peter Bailey, Nicola Waddell, John V. Pearson, Ivon Harliwong, Huamin Wang, Daniela Aust, Karin A. Oien, Ralph H. Hruban, Sally E. Hodges, Amy McElhany, Charupong Saengboonmee, Fraser R. Duthie, Sean M. Grimmond, Andrew V. Biankin, David A. Wheeler, Richard A. Gibbs, Marc D. Jones, Amanda Mawson, Christopher J. Scarlett, Mary Anne L. Brancato, Sarah J. Rowe, Skye H. Simpson, Mona Smith Martyn, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Chou Angela, Mark J. Cowley, Jeremy L. Humphris, Scott Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann Marie Patch, Sarah Song, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Christina Xu, Katia Nones, Lynn J. Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Queelly, David Wood, Nick Pavlakis, Alex Guminski, Christopher Toon, Ray Asghari, Neil D. Merrett, Darren Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O'Connnor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O'Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain, James R. Eshleman, Anirban Maitra, Christine Iacobuzio-Donahue, Richard David Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary Hodgin, Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Claudio Bassi, Margaret A. Tempero, Greater Glasgow, Janet S. Graham

Research output: Contribution to journalArticle

Abstract

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

Original languageEnglish (US)
Pages (from-to)907-919
Number of pages13
JournalCell Reports
Volume14
Issue number4
DOIs
StatePublished - Feb 2 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Gingras, M. C., Covington, K. R., Chang, D. K., Donehower, L. A., Gill, A. J., Ittmann, M. M., Creighton, C. J., Johns, A. L., Shinbrot, E., Dewal, N., Fisher, W. E., Pilarsky, C., Grützmann, R., Overman, M. J., Jamieson, N. B., Van Buren, G., Drummond, J., Walker, K., Hampton, O. A., ... Graham, J. S. (2016). Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation. Cell Reports, 14(4), 907-919. https://doi.org/10.1016/j.celrep.2015.12.005