Abstract
Genomic analyses of human cells expressing dihydrofolate reductase provide insight into the effects of genome position on the propensity for a drug-resistance gene to amplify in human cells.
Highlights
Amplifications, regions of focal high-level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors
Translated to human disease, these studies suggest that genome context together with the particular challenges to genome stability experienced during the progression to cancer contribute to the propensity to amplify a specific oncogene, whereas the overall functional response to drug challenge may be independent of the genomic location of an oncogene
The HCT116+chr3 cells are a variant of the mismatch repair deficient colorectal carcinoma cell line, HCT116; they are mismatch repair proficient due to the wild-type copy of MLH1 provided by an extra copy of chromosome 3p and proximal 3q [17,18]. Because these cells carry two wildtype copies of DHFR, we introduced a mutant form of DHFR (L22F), which confers greater resistance to methotrexate than the wild-type gene, into HCT116+chr3 cells by retroviral infection
Summary
Amplifications, regions of focal high-level copy number change, lead to overexpression of oncogenes or drug resistance genes in tumors Their presence is often associated with poor prognosis; the use of amplification as a mechanism for overexpression of a particular gene in tumors varies. Amplifications, regions of focal high level copy number change, are likely to represent aberrations continuously under selection during tumor growth, since amplified DNA is unstable [1,2,3,4] and would otherwise disappear. They often harbor known oncogenes and are useful for identifying genes or pathways that foster tumor development.
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