Put A Cap On It

If you’re not too selective in your reading you may have spotted ‘a new test which can predict with 100 per cent accuracy whether a person will develop cancer up to 13 years in the future’ trumpeted, needless to say, by The Telegraph and The Independent. No one with much of a clue about biology would write such a line and, somewhat surprisingly, it was left to the Daily Mail to produce a more balanced account of a study from Northwestern University that measured the length of telomeres in blood over time to see if that could be used as a marker for cancer development.

How long is a cap?

Telomeres: protective DNA caps on the ends of chromosomes

Telomeres: protective DNA caps on the ends of chromosomes

Telomeres are short, repeated sequences of DNA that ‘cap’ the ends of our 46 chromosomes but the cell machinery that makes DNA can’t manage to replicate the tips of the caps, so every time a new cell is made the ends of each telomere get lost. Which is of no matter to individual cells (as telomeres don’t code for protein) but their continuing loss in all cells would mean the species couldn’t survive. Accordingly, germline cells (through which sexual reproduction occurs) make an enzyme called telomerase that can achieve the trick of replicating the ends of chromosomes. In all other types of cell, however, telomerase is almost undetectable—its gene is still present, of course, but its almost completely ‘switched off,’ never to be turned on again. Never, that is, unless the cell becomes a tumor cell – most primary tumours make substantial amounts of telomerase, so they can maintain the length of their telomeres and can grow indefinitely.

The new study showed, as expected, that the telomeres in white blood cells get shorter with age but the striking finding was that, on average, shortening happens a shade more rapidly in individuals who went on to develop cancer than in those who did not. However, for the cancer group in the three to four years before diagnosis telomere attrition ceased, cap length becoming relatively stable, presumably as a result of telomerase being switched on. In other words, it seems that cancer development may actually increase telomere shortening in the period before telomerase kicks in to maintain ‘immortality’ in the tumour cell. The presumption is that this effect shows up in white cells in circulating blood because at least some of them will have encountered the ‘tumour microenviroment’ that we visited last time.

And the truth of the matter …

Do these results justify the headlines that (yet again) so annoyed me? As ever, it’s not a bad idea to read what the boffins who did the work actually said about their study, to wit, that it “… enabled us to establish temporal associations between blood telomere length and cancer risk … However, our findings should be confirmed in future studies. Our sample size limited our ability to analyze specific cancer subtypes other than prostate cancer. Thus, caution should be exercised in interpreting our results as different cancer subtypes have different biological mechanisms, and our low sample size increases the possibility of our findings being due to random chance and/or our measures of association being artificially high.”

Well said lads: no hype there, just an honest assessment – but bear in mind if you ever tire of science you’ll never get a job as a journalist.

Reference

Hou, L. et al. (2015). Blood Telomere Length Attrition and Cancer Development in the Normative Aging. EBioMedicine doi:10.1016/j.ebiom.2015.04.008.

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POTty training for chromosomes

Our genetic material comes in chunks called chromosomes, the ends of which are capped with repetitive DNA sequences called telomeres. Every time DNA is replicated to make new cells bits of the telomeres are lost – so they get shorter – and eventually this turns on a stress signal that puts a stop to further cell reproduction. So, the older you get the shorter your telomeres become and when that stops you making more cells you conk out. Lurking within our chromosomes is a gene that can stop this happening: it encodes an enzyme called, of course, telomerase that extends chromosome caps. But, you exclaim, a well-known feature of cancer cells is that they are ‘immortal’ – so they must find a way of switching on the telomerase gene that in normal cells is turned off to ensure that we don’t hang around too long. And indeed most of them do – which highlights another of life’s balancing acts: telomerase off = finite life-span, telomerase on = cancer.

Telomeres (red) cap the ends of chromosomes

Telomeres (red) cap the ends of chromosomes

Putting a cap on it

Human telomeres contain thousands of repeats of the 6-base sequence TTAGGG that cap the ends of chromosomes. To prevent these being worn away and enable cells to become ‘immortal’, the genetic mayhem that characterizes tumours usually includes a means of activating telomerase. However, you won’t be surprised to find that extending telomeres is a complicated business and the telomerase enzyme is just one bit of a multi-component molecular machine that does the job. One of the bits is a protein by the name of POT (POT1 to be precise) and a Spanish group have just shown that mutations in POT1 occur in chronic lymphocytic leukemia. Normal POT1 acts as a negative regulator that suppresses telomere extension: mutations in POT1 permit telomere extension and also enable chromosomes to fuse end-to-end with one another – a common type of genetic damage in leukemia. It appears that, although POT1 mutations are quite rare, they occur only in the clinically aggressive subtype of CLL – so they provide not only a new potential drug target but also a prognostic indicator.

Incidentally, despite what you might think, ‘cancer genes’, i.e. genes that by acting abnormally (as a result of suffering some sort of mutation, either in themselves or indirectly) can help to drive cancer development, have names that are very sensible and logical. Thus POT1 stands for protection of telomere – and it’s POT1 just in case a close rello turns up – which would be POT2.

Reference

Ramsay, A.J. et al., (2013). POT1 mutations cause telomere dysfunction in chronic lymphocytic leukemia. Nature Genetics 45, 526–530.

http://www.readcube.com/articles/10.1038/ng.2584?locale=en