CANCER AND CHROMOSOMAL TRANSLOCATIONS
Burkitt’s lymphoma is characterised by chromosomal translocations involving the MYC gene but, in contrast to BCR-ABL1 in CML, these re-arrangements do not affect the encoded protein. So normal MYC is produced but its control is changed. The culprits in Burkitt’s lymphoma are regions of immunoglobulin genes that find themselves juxtaposed to MYC. Sometimes translocated MYC may also pick up mutations that have some effect on its function or on the half-life of its mRNA, but the main feature of this type of mutation is that normal MYC finds itself regulated by a DNA sequence that usually controls a completely different gene.
The converse of duplication is deletion – that is the complete loss of a segment of DNA that includes a gene or genes. At first glance, it may seem improbable that the loss of a gene, and hence the protein encoded, might promote cancer. However, we have seen several examples of how biological systems involve equilibria between forces pushing in opposite directions. Nowhere is this truer than in the cell cycle, which is driven forwards (cell proliferation) by the action of cyclin-dependent kinases but is also subject to negative regulation – that is, there are proteins that can hold up progression through the cycle.
Another major priority is that division should not occur before DNA has replicated and that this should not happen if the DNA is damaged in any way. Accordingly, there are proteins that, in effect, arrest the cell cycle until the correct signals are received and until any DNA damage has been repaired. These proteins act as brakes and it’s easy to see that if they are lost the cell will lose a regulator of normal division and become cancer-prone. The genes that encode such proteins are called tumour suppressor genes and they comprise the second major group of ‘cancer genes’. These evolved to control normal cell growth, so they’re not really ‘tumour suppressor’ genes at all: a more appropriate name might be ‘growth suppressor’ genes. The critical point, however, is that key members of this family are often disabled in cancers – commonly by loss of the entire gene or even a complete chromosome, although sometimes less drastic mutations also impair their function (e.g. a single base change in the promoter of the retinoblastoma gene, RB1, can block its transcription). Glioblastomas, the most common and aggressive type of human brain tumour, have very often lost one complete copy of chromosome 10 and with it at least two tumour suppressor genes, PTEN and ANXA7. In losing chromosome 10, glioblastomas also frequently have extra copies of part of chromosome 7: the amplified DNA includes the EGFR gene that, as we’ve seen, is a powerful oncogene when over-expressed or mutated.