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

Gingras, Marie‐Claude; Covington, Kyle R.; Chang, David K.; Donehower, Lawrence A.; Gill, Anthony J.; Ittmann, Michael; Creighton, Chad J.; Johns, Amber; Shinbrot, Eve; Dewal, Ninad; Fisher, William E.; Pilarsky, Christian; Grützmann, Robert; Overman, Michael J.; Jamieson, Nigel B.; Buren, George Van; Drummond, Jennifer; Walker, Kimberly; Hampton, Oliver A.; Liu, Xi; Muzny, Donna M.; Doddapaneni, Harshavardhan; Lee, Sandra L.; Bellair, Michelle; Hu, Jianhong; Han, Yi; Dinh, Huyen; Dahdouli, Mike; Samra, Jaswinder S.; Bailey, Peter J.; Waddell, Nicola; Pearson, John V.; Harliwong, Ivon; Wang, Huamin; Aust, Daniela E.; Oien, Karin A.; Hruban, Ralph H.; Hodges, Sally E.; McElhany, Amy L.; Saengboonmee, Charupong; Duthie, Fraser; Grimmond, Sean M.; Biankin, Andrew V.; Wheeler, David A.; Gibbs, Richard A.

doi:10.1016/j.celrep.2015.12.005

Cited by 110 publications

(120 citation statements)

References 50 publications

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“…like 5p amplification of ampulla, 3q amplification of bile duct, and 13p amplification of duodenum (32). These sites of origin specific aberrations were not unique in our cohort, where 13p amplification of duodenum was frequently observed in the ampulla of intestinal type.…”

Section: Discussionsupporting

confidence: 49%

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

et al. 2016

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Despite advances in diagnostics, less than 5% of patients with periampullary tumors experience an overall survival of five years or more. Periampullary tumors are neoplasms that arise in the vicinity of the ampulla of Vater, an enlargement of liver and pancreas ducts where they join and enter the small intestine. In this study, we analyzed copy number aberrations using Affymetrix SNP 6.0 arrays in 60 periampullary adenocarcinomas from Oslo University Hospital to identify genome-wide copy number aberrations, putative driver genes, deregulated pathways, and potential prognostic markers. Results were validated in a separate cohort derived from The Cancer Genome Atlas Consortium (n ¼ 127). In contrast to many other solid tumors, periampullary adenocarcinomas exhibited more frequent genomic deletions than gains. Genes in the frequently codeleted region 17p13 and 18q21/22 were associated with cell cycle, apoptosis, and p53 and Wnt signaling. By integrating genomics and transcriptomics data from the same patients, we identified CCNE1 and ERBB2 as candidate driver genes. Morphologic subtypes of periampullary adenocarcinomas (i.e., pancreatobiliary or intestinal) harbor many common genomic aberrations. However, gain of 13q and 3q, and deletions of 5q were found specific to the intestinal subtype. Our study also implicated the use of the PAM50 classifier in identifying a subgroup of patients with a high proliferation rate, which had impaired survival. Furthermore, gain of 18p11 (18p11. 21-23, 18p11.31-32) and 19q13 (19q13.2, 19q13.31-32) and subsequent overexpression of the genes in these loci were associated with impaired survival. Our work identifies potential prognostic markers for periampullary tumors, the genetic characterization of which has lagged.

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Section: Discussionsupporting

confidence: 49%

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

et al. 2016

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“…KRAS mutations composed the largest majority of the SAs, with PIK3CA , MDM2 amplification, and ERBB2 amplification also identified in a significant proportion of the patients. In addition, inactivating mutations in ELF3 , which were previously found to be oncogenic in AC, were also found in our cohort . Figure shows an OncoPrint of SAs with the highest OncoKB found for the total cohort …”

Section: Resultssupporting

confidence: 71%

Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes

Wong

Lowery

Berger

et al. 2019

Cancer

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Background Ampullary carcinoma (AC) is a rare gastrointestinal cancer. Pathogenic germline alterations (PGAs) in BRCA2 and potentially targetable somatic alterations (SAs) in ERBB2 and ELF3 have been previously described in AC. Memorial Sloan Kettering Cancer Center has implemented an opt‐in strategy for germline testing (GT) and somatic testing (ST) for patients with AC to further evaluate the spectrum of PGAs and SAs. Methods Forty‐five patients with pathologically confirmed AC prospectively consented with the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT) test (410‐468 genes). A subset of the cohort (23 of the 45 patients) also consented to GT with MSK‐IMPACT (76‐88 genes). Germline data for 21 of the remaining 22 patients who had not consented to GT were obtained in a de‐identified fashion without clinical correlation. Clinicopathologic features, treatment histories, and survival data for consenting patients were collected and analyzed. Results Pancreaticobiliary, intestinal, and mixed features of the 2 types were the primary pathologic subtypes of AC identified in this cohort. No difference in median overall survival was found between pathologic subtypes. Eight of 44 patients (18%) were identified as harboring pathogenic mutations in BRCA2, ATM, RAD50, and MUTYH. In addition, this study found a wide spectrum of SAs in genes such as KRAS, MDM2, ERBB2, ELF3, and PIK3CA. Two patients in the cohort underwent SA‐targeted therapy, and 1 had a partial radiographic response. Conclusions Mutations in multiple somatic and germline genes were identified in this cohort. Significantly, actionable targets were identified in the tumors, and broader testing for PGAs and SAs should be considered for all patients with AC.

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“…ELF3 was another novel candidate driver gene identified in this study 92 , primarily in pCCA/dCCA. Inactivating mutations in ELF3 have since been identified in dCCA samples in two other genomic analyses 98,99 ; thus, the ETS-related transcription factor ELF3 probably acts as a tumour suppressor in cholangiocarcinoma. In keeping with data reported by Nakamura et al 92 , targeted sequencing of selected cancer-related genes in a study of 28 iCCA samples revealed potentially actionable alterations in IDH1 , IDH2, FGFR2 , KRAS , PTEN , and CDKN2A , among others 95 .…”

Section: Emerging Molecularly-directed Therapiesmentioning

confidence: 99%

Cholangiocarcinoma — evolving concepts and therapeutic strategies

et al. 2017

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Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.

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

Cited by 110 publications

References 50 publications

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

The Genomic Landscape of Pancreatic and Periampullary Adenocarcinoma

Ampullary cancer: Evaluation of somatic and germline genetic alterations and association with clinical outcomes

Cholangiocarcinoma — evolving concepts and therapeutic strategies

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