Chromosomal translocations point the way toward personalised cancer care
Breakage first or contact first hypothesis
- Date : 17 Aug 2012
- Topic : Personalised medicine
A chromosomal translocation is the exchange of genetic material between chromosomes. Some translocations cause cancer, and some translocations are targets for emerging, personalised therapies. When a broken chromosome attaches to another, or when chromosomes use a similar process to exchange genetic material, they cause a translocation – genes end up fused to other genes, encoding a new protein they shouldn’t. A recent University of Colorado Cancer Centre review article in the journal Frontiers of Medicine discusses chromosomal translocations and their impact on cancer development and possibilities for personalised care.
Cancer-causing translocations and the potential for targeting therapies
The most famous example is the Philadelphia chromosome – the translocation and fusion of genes BCR and ABL that causes chronic myeloid leukaemia (CML). Other oncogenic translocations include the fusion of genes ALK and EML4 to create ALK-positive non-small cell lung cancer. The promise of recognising these cancer-causing translocations is the potential to target cells with these genetic mutations.
According to the review’s author Prof. Jing Wang of the University of Colorado Cancer Center, since their discovery, chromosomal translocations have made a critical impact on diagnosis, prognosis and treatment of cancers. In CML, the revolutionary drug imatinib targets the translocation product, the Philadelphia chromosome; in ALK+ lung cancer, the drug crizotinib, targets the ALK. In both cases, targeted therapies kill cancerous cells with these translocations while leaving healthy cells unharmed. Recognising specific translocations can also allow doctors to offer a more accurate prognosis and may inform treatment decisions.
Still, there are many challenges in this developing science. The first is describing the mechanism of these translocations, for example, whether chromosomes that are near each other are prone to joining in ways that allow them to exchange or fuse genetic material, or if chromosomes spontaneously break. There are scientists on either side of this breakage first or contact first hypothesis.
Another challenge is discovering which translocations cause cancer and which just happen to hitchhike along with other mutations that are cancer’s true cause. Which translocations are frequent in cancer can be found from frequency data, but to discover if a translocation is oncogenic, other models are needed.
Study of chromosomal translocations
New technologies including next-generation DNA sequencing make increasingly easy to discover the genetic differences between cancerous and healthy cells. According to Prof. Wang in 20 years we’ll talk about personalising the genome, meaning that every individual cancer patient could be genetically screened for every genetic mutation and then treatment based on the signature of their mutations. But discovering which mutations matter is another story. When a mutation is pinpointed, for obvious reasons a translocation in a human can’t be created and then monitored if cancer will develop.
Even once an oncogenic translocation is discovered, it remains unsure whether the discovery will prove therapeutically useful. Sometimes these translocations might be present in healthy cells or some genes involved in translocations may be essential factors for cell survival. For example, c-myc gene is upregulated in specific type of lymphomas but targeting c-myc gene will result in very high toxicity. Or in still other cases drugging the target can be more difficult than in others.
Today’s challenge may be tomorrow’s cure. Right now we’re in the midst of a cancer care revolution toward personalised care based on a cancer’s genetic signature – and the study and exploitation of chromosomal translocations may lead the way.
This work was supported by University of Colorado School of Medicine start-up fund, Leukaemia Research Foundation and the Boettcher Foundation Webb-Waring Biomedical Research Award.
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