Gene amplification: mechanisms and involvement in cancer

Gene amplification was recognized as a physiological process during the development of Drosophila melanogaster. Intriguingly, mammalian cells use this mechanism to overexpress particular genes for survival under stress, such as during exposure to cytotoxic drugs. One well-known example is the amplification of the dihydrofolate reductase gene observed in methotrexate-resistant cells. Four models have been proposed for the generation of amplifications: extrareplication and recombination, the breakage-fusion-bridge cycle, double rolling-circle replication, and replication fork stalling and template switching. Gene amplification is a typical genetic alteration in cancer, and historically many oncogenes have been identified in the amplified regions. In this regard, novel cancer-associated genes may remain to be identified in the amplified regions. Recent comprehensive approaches have further revealed that co-amplified genes also contribute to tumorigenesis in concert with known oncogenes in the same amplicons. Considering that cancer develops through the alteration of multiple genes, gene amplification is an effective acceleration machinery to promote tumorigenesis. Identification of cancer-associated genes could provide novel and effective therapeutic targets.