GENE AMPLIFICATION AND CANCER
The duplication of entire genes occurs frequently in human cancers and was in the most common solid cancer in children – neuroblastoma. From a search for novel proto-oncogenes there emerged NMYC, which strikingly may be amplified up to 1,000-fold in advanced cases. NMYC is a close relative of MYC, a transcription factor that is essential for cell proliferation. MYC was the second oncogene to be discovered after SRC and was identified through the insight of Michael Bishop in analysing an avian myelocytomatosis virus (AMV), so called because it causes tumours in myeloid cells. The virus also induces carcinomas, the most prevalent of human cancers, so Bishop reasoned that its genome might bear something at least as exciting as Src. It was a brilliant piece of educated guesswork because the gene in question turned out to be Myc (named from myelocytomatosis). It transpired that expression of MYC is essential for mammalian cell proliferation, and it is the oncogene most frequently associated with the development of human cancers. In most types of cancer cell, the amount of MYC protein is increased relative to normal cells – in some colon cancer cells, there are over 100,000 molecules of MYC compared to fewer than 1,000 in normal cells. In most cases, this is due to over-expression of the gene (synthesis of too much protein) rather than amplification (duplication of the gene itself), although in some tumour sub-sets MYC amplification is very prevalent (e.g. in breast tumours with BRCA1 mutations). Thus mutations in MYC protein are not necessary to render MYC oncogenic although when they do occur they may enhance pathogenicity.
Gene amplification occurs as a result of errors during DNA replication but the mechanism is less important than the fact that it increases the number of copies of the normal gene. The number of duplications may range from two copies to the 1,000 sometimes found in neuroblastomas. The upshot is that more protein is made that would be produced in a normal cell. For MYC, in particular, it may be readily appreciated that if you have too much of a protein that promotes cell proliferation you might have a very good cancer driver.
The duplication of relatively long stretches of DNA within the human genome occurs quite frequently. About 5% of the human genome is made up of what’s called segmental duplications – that is, segments longer than 1,000 bases that are virtually identical in sequence to stretches found elsewhere. Segmental duplications make up more than half the Y (male) chromosome. So gene amplification in cancer is only a more extreme version of something that has been a normal part of evolution, thought to have been favoured for the increase in the genetic potential that it conferred. The prevalence and significance of this duplication is perhaps best illustrated by the fact that, from whole-genome sequencing, we now know that, on average, about 80 genes differ in copy number between the genomes of any two individuals – and that difference in gene dosage (reflected by the number of proteins made) makes a significant contribution to individual variation.