Genes co-amplified with <i>ERBB2</i> or <i>MET</i> as novel potential cancer-promoting genes in gastric cancer

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: <i>ERBB2</i> and <i>MET</i>. Correlation analysis of CNAs and gene expression levels identified <i>CAPZA2</i> (co-amplified with <i>MET</i>) and genes <i>GRB7</i>, <i>MIEN1</i>, <i>PGAP3</i>, and <i>STARD3</i> (co-amplified with <i>ERBB2</i>) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with <i>MET</i> or <i>ERBB2</i> in GC tissue samples, and revealed that high expression (except for <i>PGAP3</i>) 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 <i>CAPZA2</i> knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with <i>MET</i> or <i>ERBB2</i>, and suggests that they play a functional role in GC.