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Abstract

Abstract 

  1. Gene amplification is a frequent genetic abnormality in human cancer cells and consists of multiple extra copies of a subchromosomal region of DNA (amplicon). Amplification can be manifested cytogenetically as extrachromosomal double-minute chromosomes (dmins) or as chromosomally integrated homogeneously staining regions (HSRs).

  2. Several mechanisms have been proposed to explain the development of gene amplification. These have been based primarily on in vitro systems in which there is selection for drug resistance, so the mechanisms involved in de novo oncogene amplification may be different. Nevertheless, for gene amplification to occur, it may be necessary to have loss of cell cycle control, DNA damage or instability, and a stimulus to progress through the cell cycle.

  3. The size of the amplicon can vary from several hundred to several thousand kilobases. The amplified DNA appears to be in a head-to-tail conformation, and the germ line configuration is largely retained, with relatively few genetic rearrangements. In most cases, only a single expressed gene is consistently amplified, but in other cases, two or more genes from a given chromosomal region may confer a selective advantage, either individually or in concert.

  4. Amplification of the MYCN oncogene occurs in 20 to 25 percent of all neuroblastomas. MYCN amplification is strongly associated with advanced stages of disease and a poor outcome. Currently, the presence of MYCN amplification is used to identify patients at high risk who need the most intensive treatment.

  5. Amplification of several different genetic regions, especially 11q13 or 12q14, is found in many common types of cancer, including carcinomas of the breast, ovary, lung, head and neck, and gastrointestinal tract. The clinical significance of these findings is somewhat controversial, but in some patients, gene amplification may be associated with a more aggressive tumor behavior and a worse outcome.

  6. The most common types of genes amplified are oncogenes and drug-resistance genes. Oncogenes, however, account for the vast majority of genes amplified in human cancers. The most common oncogenes amplified are members of the MYC family, the RAS family, the EGFR family, the FGF family, and genes involved in cell cycle regulation (CCND1, CCNE, MDM2, CDK4).

  7. The mechanisms whereby oncogene amplification confers a selective advantage vary depending on the gene, but include overexpression of (a) a transcription factor (MYC family) favoring continued proliferation; (b) a signal transduction molecule (RAS family), growth factor, or receptor (EGFR, FGF families), that mimicks constitutive growth factor stimulation; or (c) cell-cycle regulatory genes (CCND1, CCNE, MDM2, CDK4) that lead to loss of cell-cycle control.

  8. There are several methods of detecting gene amplification that vary in their difficulty or the need to know the gene (or genes) likely to be amplified. These methods include (a) conventional cytogenetics; (b) Southern blotting; (c) quantitative PCR; (d) fluorescence in situ hybridization (FISH); (e) comparative genomic hybridization (CGH); and (f) microarray technology.

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