Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation - PubMed (original) (raw)

. 2016 Feb 2;14(4):907-919.

doi: 10.1016/j.celrep.2015.12.005. Epub 2016 Jan 21.

Kyle R Covington 2, David K Chang 3, Lawrence A Donehower 4, Anthony J Gill 5, Michael M Ittmann 6, Chad J Creighton 7, Amber L Johns 8, Eve Shinbrot 2, Ninad Dewal 2, William E Fisher 9; Australian Pancreatic Cancer Genome Initiative; Christian Pilarsky 10, Robert Grützmann 11, Michael J Overman 12, Nigel B Jamieson 13, George Van Buren 2nd 9, Jennifer Drummond 2, Kimberly Walker 2, Oliver A Hampton 2, Liu Xi 2, Donna M Muzny 2, Harsha Doddapaneni 2, Sandra L Lee 2, Michelle Bellair 2, Jianhong Hu 2, Yi Han 2, Huyen H Dinh 2, Mike Dahdouli 2, Jaswinder S Samra 14, Peter Bailey 15, Nicola Waddell 16, John V Pearson 16, Ivon Harliwong 17, Huamin Wang 18, Daniela Aust 19, Karin A Oien 20, Ralph H Hruban 21, Sally E Hodges 22, Amy McElhany 22, Charupong Saengboonmee 23, Fraser R Duthie 20, Sean M Grimmond 24, Andrew V Biankin 3, David A Wheeler 25, Richard A Gibbs 2

Affiliations

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

Marie-Claude Gingras et al. Cell Rep. 2016.

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.

Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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Figures

Figure 1

Figure 1. Mutation frequencies and MSI characteristics

A. Mutation frequencies for all patients by anatomical site (DUOAC, D; AMPAC, A; CAC, C) and subtype (intestinal, I; mixed, M; pancreatobiliary, PB). Black dots, microsatellite stable (MSS); red dots, microsatellite instable (MSI). B. Germline mutations in MMR gene associated with Lynch syndrome were detected in 66% of the MSI samples. Survival (m) is in months; black tile, patient died of disease; white tiles, patient alive; Lynch Mutation Freq, frequency each gene is observed in Lynch Syndrome patients; blue tiles, missense mutations; green, frame-shift mutations; red, nonsense mutations; “L” = known Lynch Syndrome mutation; “d” deleterious mutation by PolyPhen2. C. Kaplan-Meier plot for survival based on MSI status in AMPAC (log rank p = 0.04, N=96). D. Kaplan-Meier plot for survival based on MSI status in all periampullary tumors (p = 0.0028, N=160). See also Figures S1a-c and Tables S1a-e.

Figure 2

Figure 2. Mutation signature in periampullary tumors

A. Heat map of five dominant mutation signatures from NMF analysis of mutation spectrum for each subject. Intensity indicates the proportion of mutations for that subject attributed to the indicated signature. Subjects are sorted first by Signature 1 then Signature 6 from the highest to the lowest value. Only signatures with high penetrance are shown. B. Kaplan-Meier curve of survival in this cohort stratified by signature 1 levels (high, red line: signature 1 component > 10% of all mutations; low, black line: otherwise, multivariate Cox proportional hazards p = 0.001). See also Figures S2a, S2b and Table S2.

Figure 3

Figure 3. Significantly mutated genes in non MSI periampullary tumors

A. Significantly mutated genes are displayed by FDR value (MutSigCV). Genes with FDR < 0.1 are located in the left panel, genes with FDR > 0.1 but significantly inactivated are in the middle panel, and genes slightly under the significant threshold of the SMG list are in the right panel. The amount of samples for each tumor type is stacked. B. ELF3 inactivating mutations were distributed along the entire gene characteristic of a tumor suppressor, q < 1.6 × 10−11. All the mutations found in the study are represented in the figure, each mutation being found in one patient. See also Tables S3a-d.

Figure 4

Figure 4. Major altered pathways in periampullary tumors

A. Frequency of changes defined by somatic mutations or copy number loss or gain is expressed as a percentage of cases for each gene. Inactivation (blue) or activation (red) is graded in intensity by percent of patients affected. B. Genetic alterations in the significantly mutated genes grouped by pathway are illustrated for each patient. Note WNT and PI3K signaling pathways could be found in the three tumor types and in each of their subtypes, including the pancreatobilliary subtype. See also Figures S3a, S3b wherein mutations in each gene are grouped by tumor type and subtype, Figure S3c, and Tables S4a, S4b.

Figure 5

Figure 5. Relative RNA expression of WNT antagonist, agonist, and target genes

Tumors were split between those with and without WNT canonical pathway mutations as shown in the mutation panel. The level of RNA expression for each gene can be visualized in the heat map and the average expression of all the genes is summarized in the lower panel. See also Figure S4 for fusions.

Figure 6

Figure 6

A. Nexus GISTIC analysis of copy number alteration by anatomical site. Upper blue panel shows copy number gains and the lower red panel shows copy number losses for each tumor type. Blue arrows demark changes characteristic of a given anatomical site. B. Focal deletion in the promotor region and at the 5’ end of KMD4C impacts its and UHRF2 expression. Human Omni 2.5 SNP array results were analyzed in IGV (Integrative Genomics Viewer, Broad Institute). Deletions are in blue and amplifications are in red. Gene expression was analyzed by dividing the samples into 2 groups: samples with (1) or without (2) focal deletion. The color ladder on the right indicates the tumor type (pink AMPAC, purple CAC, orange DUOAC). See also Tables S6a, S6b.

Comment in

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