Genes co-amplified with ERBB2 or MET as novel potential cancer-promoting genes in gastric cancer.

Mi Jeong Kwon,Jinil Han,Jonathan R Pollack,Sinyoung Jeon,Kyoung Song,Jong-Sun Choi,Ryong Nam Kim,Young Kee Shin,Yoon-La Choi,Sungyoul Hong,Hae Min Jeong,Ensel Oh,Joo Seok Kim,Jungsuk An,Cheol-Keun Park

doi:10.18632/oncotarget.21150

Abstract

Gastric cancer (GC), one of the most common cancers worldwide, has a high mortality rate due to limited treatment options. Identifying novel and promising molecular targets is a major challenge that must be overcome if treatment of advanced GC is to be successful. Here, we used comparative genomic hybridization and gene expression microarrays to examine genome-wide DNA copy number alterations (CNAs) and global gene expression in 38 GC samples from old and young patients. We identified frequent CNAs, which included copy number gains on chromosomes 3q, 7p, 8q, 20p, and 20q and copy number losses on chromosomes 19p and 21p. The most frequently gained region was 7p21.1 (55%), whereas the most frequently deleted region was 21p11.1 (50%). Recurrent highly amplified regions 17q12 and 7q31.1-7q31.31 harbored two well-known oncogenes: ERBB2 and MET. Correlation analysis of CNAs and gene expression levels identified CAPZA2 (co-amplified with MET) and genes GRB7, MIEN1, PGAP3, and STARD3 (co-amplified with ERBB2) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with MET or ERBB2 in GC tissue samples, and revealed that high expression (except for PGAP3) was significantly associated with shorter overall survival. Knockdown of these genes using small interfering RNA led to significant suppression of GC cell proliferation and migration. Reduced GC cell proliferation mediated by CAPZA2 knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with MET or ERBB2, and suggests that they play a functional role in GC.

Highlights

Gastric cancer (GC) is one of the most common malignancies and the third most prevalent cause of cancer death worldwide [1]
This study identified novel candidate cancer-promoting gene (CPG) co-amplified with MET or ERBB2, and suggests that they play a functional role in GC
To identify DNA copy number alteration (CNA) in the GC genome we performed high-density oligonucleotide array comparative genomic hybridization of genomic DNA from 40 GC samples obtained from 19 old (O1 to O19) and 21 young patients (Y1 to Y21)

Summary

Introduction

Gastric cancer (GC) is one of the most common malignancies and the third most prevalent cause of cancer death worldwide [1]. Curative therapy with surgical resection is possible at the early stages, most patients are diagnosed with advanced disease, which has a poor prognosis [2]. The 5 year survival rate of patients with advanced GC is only 25% to 35% [3, 4], and chemotherapy remains the main treatment. Only two therapeutic antibodies, trastuzumab (which targets HER2) and ramucirumab (which targets VEGFR2), have been approved for use as treatments for GC. Clinical trials show that, compared with chemotherapy alone, addition of trastuzumab to chemotherapeutic regimens improves patient survival [5,6,7], and that ramucirumab monotherapy, or ramucirumab in combination with chemotherapy, confers survival benefits on advanced GC patients that have received prior treatments [8, 9]. A better understanding of the molecular alterations that occur during GC progression is required if we are to identify novel and promising therapeutic targets for GC

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Conclusion