Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN , MET , WNT2 , and ERBB2

Abstract

Gastric adenocarcinoma is a malignant tumor with a high incidence and a low survival rate. In order to identify genetic alterations associated with this tumor, we screened 23 gastric adenocarcinomas for recurrent chromosomal imbalances by using comparative genomic hybridization (CGH). The most common gains of chromosomal material were found on chromosome arms 20q (10 cases), 16p (7 cases), and 1q (4 cases) and on chromosome 11 (4 cases). Losses were observed on chromosome arms 4q, 5q, 9p, and 21q (3 cases each). Four tumors exhibited high‐level amplifications localized on chromosome regions 2p23–p24, 7q31–q32, 8p21–p22, 10q25–q26, 11q13, 17q11–q21, and 20q. Based on the position of these amplifications, candidate (onco)genes were selected and subsequently tested by Southern blot analysis of the respective tumors. Of the seven tested candidates, MYCN, MET, WNT2, and ERBB2 were found to participate in the amplicons of the respective tumor samples. Of these four presumably activated oncogenes, two, MYCN and WNT2, were previously not assumed to play a pathogenic role in stomach cancer. Among the other regions of imbalance, gain of 20q seems particularly interesting, because it is found in almost half of the analyzed cases and is highly amplified. Our data allowed us to narrow the relevant region down to the commonly gained bands 20q12–q13.1. This and other imbalanced regions provide a basis for searching new putative oncogenes and tumor suppressor genes involved in the development or progression of gastric adenocarcinoma. Genes Chromosomes Cancer 23:307–316, 1998. © 1998 Wiley‐Liss, Inc.

Antitumor Action of the MET Tyrosine Kinase Inhibitor Crizotinib (PF-02341066) in Gastric Cancer Positive for MET Amplification

“…The receptor tyrosine kinase MET is considered one such potential target in cancer, and several MET-TKIs are currently undergoing clinical trials in humans. Amplification of MET is often responsible for activation of MET signaling, with such amplification occurring frequently in gastric cancer (4)(5)(6). We have now shown that crizotinib exerted a marked antitumor action in gastric cancer cells with MET amplification.…”

“…Substantial advances in the development of molecularly targeted therapies for gastric cancer have been achieved in recent years (3). Amplification of the proto-oncogene MET is a frequent molecular abnormality in gastric cancer (4)(5)(6), and a MET-tyrosine kinase inhibitor (TKI) has been shown to induce apoptosis in gastric cancer cells with MET amplification (7,8).…”

Molecular Genetic Changes in Metastatic Primary Barrett's Adenocarcinoma and Related Lymph Node Metastases: Comparison with Nonmetastatic Barrett's Adenocarcinoma

“…Previous CGH studies of adenocarcinomas of the stomach and the gastroesophageal junction have revealed gain on 22q in a low frequency (7,30,31). In addition, colorectal and gastric carcinomas frequently have loss of heterozygosity on chromosome 22q, suggesting that inactivation of tumor suppressor genes on 22q participates in the tumor development (32).…”

MET and MYC cooperate in mammary tumorigenesis

“…MYC has been implicated in many types of human cancer, and it is overexpressed in a subset of breast cancers (33). Although MET and MYC loci are coamplified in some gastric cancers (34,35), it is not known whether MET and MYC are cooverexpressed or whether these genes cooperate in the genesis of breast cancer.…”