Genomic amplification of MET with boundaries within fragile site FRA7G and upregulation of MET pathways in esophageal adenocarcinoma

Abstract

Esophageal adenocarcinoma (EA) is characterized by a poor prognosis making the identification of clinically targetable proteins essential for improving patient outcome. We report the involvement of multiple alterations of the MET pathway in EA development and progression. Microarray analysis of Barrett's metaplasia, dysplasia, and EA revealed overexpression of the MET oncogene in EAs but only those with MET gene amplification. STSamplification mapping revealed that the boundary of the MET amplicon in these EAs is defined by fragile site FRA7G. We also identified an amplicon at 11p13 that resulted in amplification and overexpression of CD44, a gene involved in MET autophosphorylation upon HGF stimulation. Tissue microarrays with phospho-METspecific antibodies demonstrated a uniformly high abundance of MET activation in primary EA and cells metastatic to lymph nodes but to a lesser extent in a subset of metaplastic and dysplastic Barrett's samples. Increased expression of multiple genes in the MET pathway associated with invasive growth, for example, many MMPs and osteopontin, also was found in EAs. Treatment of EA-derived cell lines with geldanamycin, an inhibitor for tyrosine kinases including MET receptor kinase, reduced cell migration and induced EA cell apoptosis. The data indicate that upregulation of the MET pathway may contribute to the poor outcome of EA patients and that therapeutic agents targeting this pathway may help improve patient survival.

MET is a potential target for use in combination therapy with EGFR inhibition in triple-negative/basal-like breast cancer

“…One particular translocation, the translocated promoter region-MET translocation, and MET amplification have been reported in gastric, oesophageal and non-small cell lung cancers. [9][10][11][12] Germ-line and somatic MET mutations are found in papillary renal, gastric and childhood hepatocellular cancers. [13][14][15] However, constitutive MET activation is primarily induced by transcriptional up-regulation or HGF-dependent autocrine/paracrine loop mechanisms.…”

Cell-Autonomous and Non–Cell-Autonomous Mechanisms of HGF/MET–Driven Resistance to Targeted Therapies: From Basic Research to a Clinical Perspective

“…Or, alternatively, did the drug induce a stress able to promote DNA breaks in fragile sites such as the one in which the MET gene is located ( 34 )? To answer these questions, Turke and colleagues ( 35 ) analyzed the HCC827 NSCLC cell line that, upon gefi tinib treatment, became resistant via MET amplifi cation.…”

Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas

“…[1][2][3] However, to date, it is thought that somatic mutation of MET is a rare event in the sporadic primary carcinomas of adults, including ovarian carcinomas, 4,5 with papillary carcinoma of the kidney being an exception. 6 On the other hand, MET amplification was identified in 5-10% of gastric cancers, 7-9 4% of esophageal cancers, 10 3-4% of lung cancers, 11,12 and 10% of colorectal cancers. 13 Our recent study identified that MET overexpression and gene amplification were commonly detected in ovarian clear-cell adenocarcinoma, with their frequencies at 22 and 24%, respectively.…”