Gene amplification in carcinogenesis

Abstract

Gene amplification increases the number of genes in a genome and can give rise to karyotype abnormalities called double minutes (DM) and homogeneously staining regions (HSR), both of which have been widely observed in human tumors but are also known to play a major role during embryonic development due to the fact that they are responsible for the programmed increase of gene expression. The etiology of gene amplification during carcinogenesis is not yet completely understood but can be considered a result of genetic instability. Gene amplification leads to an increase in protein expression and provides a selective advantage during cell growth. Oncogenes such as CCND1, c-MET, c-MYC, ERBB2, EGFR and MDM2 are amplified in human tumors and can be associated with increased expression of their respective proteins or not. In general, gene amplification is associated with more aggressive tumors, metastases, resistance to chemotherapy and a decrease in the period during which the patient stays free of the disease. This review discusses the major role of gene amplification in the progression of carcinomas, formation of genetic markers and as possible therapeutic targets for the development of drugs for the treatment of some types of tumors.

Estrogen receptor alpha gene amplification in breast cancer: 25 years of debate

“…To gain clarity on the prevalence of gene amplification requires first that the term be defined. In general, "gene amplification" is defined as an increase in the gene copy number in a cell, independent of the ratio of gene copy number to centromere copy number [43,44] . However, as testing for human epidermal growth factor receptor 2 (HER2, ERBB2) became more frequent, the term "gene amplification" was reserved for amplifications with an average gene to centromere ratio of ≥ 2.0 or ≥ 2.2 (or > 6 copies per nucleus), simply because the threshold for predicting the response to therapy was determined at this level [45][46][47] .…”

“…Expression of the ERα-protein itself has long been used for decades as a biomarker for initiating anti-estrogen treatment in breast cancer [9] . However, regardless of the prevalence of gene amplification across a tumor type, the increase in copy number for a given gene is a well-known mechanism for increasing its expression [16,17,44,92,93] ; accordingly, gene amplification is assumed to be a marker for a tumor's addiction to the expression of the amplified gene [18,19] . Several reports, including those that use DNA-specific methods for ESR1 copy number determination, have documented a significant correlation between ESR1 gene amplification and ERα protein expression [24,25,28,50,67,[83][84][85][86][87][88][89][90][91][92][93][94][95][96][97] ( Table 1).…”

Association Between Amplification and Expression of C-MYC Gene and Clinicopathological Characteristics of Stomach Cancer

“…A gene copy number of four to six copies per nucleus in at least 50% of cancer cells were considered as “moderate level amplification” ( Figure 1C ). A gene copy number of more than six copies per nucleus or the presence of clusters in at least 50% of cancer cells was considered as “high-level amplification” ( Figure 1D ) ( 18 , 19 , 27 ). Non-neoplastic cells in tissues were always considered as in-test quality controls.…”

“…This indicates that the levels of MYC-MAX heterodimer are constantly regulated by the current of mitogenic signals, which normal cells receive ( 16 ). The MYC gene has three exons, and its protein products (p64 and p67) include strongly conserved nuclear phosphoproteins, with high amounts of p64 compared with p67, called MYC-2 and MYC-1, respectively ( 18 ).…”

Relationship of Amplification and Expression of the C-MYC Gene with Survival among Gastric Cancer Patients

“…A gene copy number of 4 to 6 copies per nucleus, in at least 50% of cancer cells, were considered as "moderate amplification" (Figure 1C). A gene copy number of more than 6 copies per nucleus or the presence of clusters in at least 50% of cancer cells, was accunted as "high amplification" (Figure 1D) (Tsuboi et al, 1987;Bizari et al, 2006;Shah and Ajani, 2010). Normal cells in tissues were considered as controls.…”