Association between TL in peripheral blood and cancer risk: the need for analytically validated biomarkers
The association of telomere length (TL) and cancer risk is still under debate and a clear relationship remains inconclusive.
First, let´s introduce what a telomere is and its importance for cell´s homeostasis.
Telomeres are repetitive non-coding nucleoprotein complexes that are located at the ends of linear chromosomes providing a protective cap. Telomeres are essential for normal cellular functioning as they maintain the integrity of the genome and prevent the loss of genetic material that resides near the ends of the chromosomes. Cellular proliferation progressively erodes telomeres and biological and environmental stressors can increase this attrition rate. In human somatic cells without telomerase activity, telomere genetic material would lose approximately 30-200 bp after each mitotic cycle because of the asymmetric replication of DNA. Measuring the TL variation is emerging as a potential biomarker to assess the relationship between various stressors and diseases as cancer.
The elusive evidence for a robust relationship between TL and malignant diseases could be due to the dual role that telomeres play in cancer; on the one hand, short telomeres induce genome instability which in many cancers is relevant and is associated with prognosis and response to treatment yet, on the other hand, all cancers mess up with telomere maintenance mechanisms (telomerase activity or Alternative Lengthening of Telomeres) to become immortal, allowing unlimited cell replication.
In cancer, many studies tried to stablish a relationship between TL in peripheral blood cells and cancer, but a meta-analysis, performed with all those studies is really complicated due to different DNA extraction methods and measurement procedures.
A study looking at data from 28 prospective studies from 25 different publications on TL and cancer risk concludes that there is a relationship between TL and cancer risk pointing out more significant result when precise methods for both -DNA isolation and TL measurement, were used.
The authors also noticed that, if stratified by gender, only men with longer TL had a significantly higher risk of cancer, yet an explanation for this situation remains unknown and gender data needs further investigation.
Overall this meta-analysis supports the viewpoint that longer TL is related to higher cancer risk, which is compatible with known biology; first, telomere elongation must rely on telomerase activity, but telomerase may have telomere-independent functions when reactivated in carcinogenesis. As an example of those functions, telomerase directly regulates NF-κB-dependent gene expression, such as that of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression.
In summary, a marginal association was concluded with the stronger detected in lung cancer and in men.
The analytical validation of the technologies used in the different studies is one of the weakest points. Moreover, no data on % of short telomeres was reported. In the field of biomarkers –as we heard recently at ESMO, using analytical validated techniques is paramount to achieve subsequent clinical validation and ensure their clinical utility. ONCOCHECK is using ISO15189/ US-CLIA certified protocols that assess not only TL but also the percentage of short telomeres as well as telomerase activity. Taking in account TL, telomerase activity and % of short telomeres we will be able to provide critical information on individual´s telomere biology in the context of cancer, which may represent one of the most remarkable biomarkers in the near future.