Abstract IA03: New assays, old specimens: Telomere length and activity.
Authors: Doherty Jennifer Anne 
Published: August 2013

Telomeres are chromatin structures that cap chromosome ends and protect the genetic integrity of cells. They progressively shorten with every cell division, and cells will generally undergo apoptosis or senescence after their telomeres reach a critically short length. If these pathways are bypassed, cells can continue replicating with concomitant telomere shortening, resulting in crisis, in which there is rampant chromosomal instability and cell death. However, a very few cells may survive crisis, and become immortalized by activation of a telomere maintenance mechanism (usually, telomerase activation). This subset of cells with genomic instability and telomere maintenance could progress towards malignant transformation1.

Telomere length is influenced by genetic, epigenetic, and environmental factors. Shorter telomere length is associated with increasing age, exposure to cigarette smoke, oxidative stress and male gender, and varies by genetic ancestry. After accounting for these factors, telomere length is still highly variable among individuals. Different chromosomes and chromosome arms of the same chromosome have varying telomere length. Telomere length also varies considerably between organ sites, likely due to the difference in cellular turnover rates.

Global telomere length can be measured using a variety of assays, including: southern blotting, which requires a large amount of DNA and is considered to be the “gold standard”; quantitative fluorescence in situ hybridization (qFISH), which is used to assay cells from fresh blood or tissue but can also be used to assay paraffin-embedded samples when combined with immunofluorescence to identify specific cell types; and real-time quantitative PCR (qPCR), which is higher throughput and can be applied to stored DNA samples. The qPCR methods tend to suffer from high coefficients of variation, and several different approaches have been developed to address this limitation. Both qFISH and qPCR methods can be modified to measure chromosome arm-specific telomere length2.

Shortened telomere length (for the most part, measured in peripheral blood) has been reported to be associated with increased risk of several cancer types. These associations are generally stronger in case-control studies than in prospective studies. Also, a growing number of publications are reporting that longer telomere length is associated with increased risk of cancer3. Questions remain about whether associations with telomere length can be explained by other factors.

While telomerase is expressed in over 90% of cancers and in some precursor lesions, its expression is weak or undetectable in most normal cells other than germ cells, stem cells and activated T cells and monocytes. To date, it is unclear whether or not peripheral lymphocyte telomerase activity is associated with increased cancer risk. Nonetheless, multiple genetic variants in the TERT locus (which encodes telomerase) are clearly associated with a number of different cancer types. In summary, several lines of evidence support the possibility that telomere length and telomerase activity may be causally associated with risk of some types of cancer, but additional prospective studies are needed, with careful attention to the assays used.

Citation Format: Jennifer Anne Doherty. New assays, old specimens: Telomere length and activity. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr IA03.