Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation

Gingras, M.-C. et al. (2016) Ampullary cancers harbor ELF3 tumor suppressor gene mutations and exhibit frequent WNT dysregulation. Cell Reports, 14(4), pp. 907-919. (doi:10.1016/j.celrep.2015.12.005) (PMID:26804919) (PMCID:PMC4982376)

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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.

Item Type:Articles
Additional Information:We acknowledge the following funding support: HGSC-BCM: NHGRI U54 HG003273 and CPRIT grant RP101353-P7 (Tumor Banking for Genomic Research and Clinical Translation Site 1); D.W.A. CPRIT grant RPI21018; M.M.I. and C.J.C.: Dan L. Duncan Cancer Center NIH P30 Cancer Center support grant (P30 CA125123) supporting the BCM Human Tissue Acquisition and Pathology Core and the Biostatistics and Bioinformatics Core; M.J.O.: Kavanagh Family Foundation. Australian Pancreatic Cancer Genome Initiative: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Institute for Molecular Bioscience; Cancer Research UK (C596/A18076, C29717/A17263); University of Glasgow; Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW: (SRP06-01, SRP11-01. ICGC); Cancer Institute NSW: (10/ ECF/2-26; 06/ECF/1-24; 09/CDF/2-40; 07/CDF/1-03; 10/CRF/1-01, 08/ RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/ 1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; Howat Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation – INNOVATOR Award; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB Associazione Italiana Ricerca Cancro (12182); Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001); Wilhelm Sander Stiftung 2009.039.2; NIH grant P50 CA62924.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jamieson, Dr Nigel and Chang, Dr David and Bailey, Dr Peter and Fisher, Mr William
Authors: Gingras, M.-C., Covington, K. R., Chang, D., Donehower, L. A., Gill, A. J., Ittmann, M. M., Creighton, C. J., Johns, A. L., Shinbrot, E., Dewal, N., Fisher, W., Pilarsky, C., Grützmann, R., Overman, M. J., Jamieson, N., Van Buren, G., Drummond, J., Walker, K., Hampton, O. A., Xi, L., Muzny, D. M., Doddapaneni, H., Lee, S. L., Bellair, M., Hu, J., Han, Y., Dinh, H. H., Dahdouli, M., Samra, J. S., Bailey, P., Waddell, N., Pearson, J. V., Harliwong, I., Wang, H., Aust, D., Oien, K. A., Hruban, R. H., Hodges, S. E., McElhany, A., Saengboonmee, C., Duthie, F. R., Grimmond, S. M., Biankin, A. V., Wheeler, D. A., and Gibbs, R. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cell Reports
Publisher:Elsevier (Cell Press)
ISSN:2211-1247
ISSN (Online):2211-1247
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in Cell Reports 14(4):907-919
Publisher Policy:Reproduced under a creative commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)18076RI CANCER SCIENCES
645511Genotype Guided Stratified Therapy for Pancreatic CancerAndrew BiankinCancer Research UK (CAN-RES-UK)17263ICS - TRANSLATIONAL RESEARCH CENTRE

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