Telomeres are to chromosomes what plastic caps are to the ends of shoelaces – they stop them unravelling as they age. Without telomeres, chromosomes would gradually lose their genetic information as cells replicate. For this reason – backed by some research – scientists believe longer telomeres are better for health. But now a new genomic study suggests longer telomeres may also increase the risk of developing deadly brain cancers known as gliomas.
Led by the University of California San Francisco (UCSF), the study focuses on two common variants of telomere-related genes known as TERT and TERC that lead to longer telomeres. TERT is carried by 51% of people and TERC is carried by 72%.
However, it is rather unusual for common variants to increase risk of disease, so the researchers suggest perhaps a genetic balancing act is going on between benefit and risk. On the benefit side, carrying longer telomere variants generally promotes overall health, while on the risk side, carrying them can also raise risk of high-grade gliomas, but for most carriers, the benefit trumps the risk, as gliomas, although nearly always fatal, are relatively rare.
“There are clearly high barriers to developing gliomas, perhaps because the brain has special protection,” explains senior author, Margaret Wrensch, professor of Neurological Surgery and Epidemiology and Biostatistics at UC San Francisco, who with colleagues reports the findings in the journal Nature Genetics.
To illustrate the point, she notes that the comment “I’ve never been sick in my life,” is not uncommon from people diagnosed with glioma.
One explanation for this genetic balancing act between benefit and risk could be that in general, slowing cellular aging is good for overall health. But perhaps this also means some cells will live longer than they are supposed to, which is a hallmark of cancer.
In a large genomic dataset that the researchers used in their analysis, covering 40,000 people, they found shorter telomeres were linked to higher risk of cardiovascular disease – a good example of where longer telomeres are generally linked to better health.
But first, the team analyzed another genome-wide dataset from 1,644 glioma patients and 7,736 healthy controls. This confirmed an already established link between TERT and gliomas, but also, for the first time, identified TERC as a glioma risk.
As it had already been established that both these genes help regulate telomerase – an enzyme that controls telomere length – the team then looked at the other, larger, dataset and found the same variants tied to glioma risk were also linked to longer telomeres.
Ever since Elizabeth Blackburn, a professor of biochemistry and biophysics at UCSF, and colleagues solved the puzzle of how chromosomes stop themselves degrading when they replicate – and also won the 2009 Nobel Prize in Physiology or Medicine for it – there have been many studies looking at links between telomere length and health and aging, and also diseases like cancer.
For example, Prof. Blackburn and colleagues released several studies showing that shortened telomeres are linked to exposure to stress.
Also, because cancer cells keep themselves alive longer by keeping their telomeres long, drug companies have been searching for compounds that can target and block telomerase in tumors – in the hope that the ends of cancer cells’ chromosomes begin to unravel so they accumulate genetic damage and die.
An example of this avenue of research is a study published in September 2013, where scientists at the University of California Santa Cruz used a new technique to reveal structural and mechanical properties of telomeres that could help the development of anti-cancer drugs.
This latest study should extend the research beyond gliomas, says the team. This is because TERT variants have also been implicated in other cancers, including of the prostate, lung, testicle and breast, and TERC variants in colon cancer, leukemia and multiple myeloma. Plus, variants in both genes have been linked to raised risk of the progressive lung disease idiopathic pulmonary fibrosis.
In some of these diseases, the variants make the telomeres longer, and in others, they make them shorter, so the authors conclude that “both longer and shorter telomere length may be pathogenic, depending on the disease under consideration.”