Transcriptional inactivation of specific genes via aberrant promoter hypermethylation

of CpG islands, causing permanent gene silencing, is a major epigenetic event in carcinogenesis. Reported genes whose expression was downregulated in GC by promoter hypermethylation are CDH1 [9], RELN [36], PTCH1a [37], HLA class I [38], CLDN11 [39], SFRP5 [40], and probably CEBPA, because it does not harbor gene mutations that could explain Kinase Inhibitor Library its downregulation in about 30% of GCs [41]. MSI is defined as the presence of replication errors in simple repetitive microsatellite sequences because of the defects in mismatch repair genes [10,42]. Many cancer-associated genes have been found to harbor mutations at mono- or dinucleotide repeats in the coding sequences in cancers with MSI [42], and GC is no exception [43]. Recently, Velho et al. [44] reported that in MSI gastric tumors, MLK3, a gene that codifies a kinase involved in MAP kinase pathway, is frequently found mutated. Noteworthy, they found that the missense mutations found in MLK3 harbor transforming and tumorigenic potential, in vitro and in vivo.

Autophagy-related genes ATG2B, ATG5, ATG9B, and ATG12 were also reported as harboring mutations in MSI tumors, contributing to cancer development by deregulation of the autophagy buy CH5424802 process [45]. Despite recent advances in perioperative and adjuvant chemotherapy, most patients with advanced disease have a median survival of less than a year. The best prognostic check parameters of the disease are TNM-staging (invasion depth and metastasis to lymph nodes or to distant sites) and complete surgical removal of the neoplastic tissue. However, these traditional prognostic clinicopathological characteristics provide limited information about predictive measures of the disease. So far, genome-wide screens have provided no clinically applicable predictive value in GC, and partly owing to this, it has been more promising to focus on specific targeted cancer treatment modalities and methods to identify their molecular targets. Several of these novel treatment options

and their putative predictive markers have not yet been proven to show clinical value in GC (for example cyclooxygenase-2 and nonsteroidal anti-inflammatory drugs or antibodies and small molecular inhibitors of epidermal growth factor receptor and amplification or mutations of the receptor). However, HER-2 has been recently demonstrated to be a molecular target in GC. Cell proliferation is tightly regulated through cellular signal transduction pathways, and growth factors and their receptors play an important role in regulation of these intracellular responses. One central family of growth factor receptors are the four related proteins named HER/ErbB receptors [46,47]. Each of these receptors are transmembrane proteins, and HER-1, HER-2, and HER-4 have an intracellular domain with tyrosine kinase activity.