Abstract
Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. TMM depends on the cancer type. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development.Methods: We have studied alterations of telomere length, their sequence composition and transcriptional regulation in mismatch repair deficient colorectal cancers arising in Lynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC), and for comparison, in microsatellite stable (MSS) s-CRC and in benign colon mucosa. Our study applied bioinformatics analysis of whole genome DNA and RNA sequencing data and a pathway model to study telomere length alterations and the potential effect of the “classical” telomerase (TEL-) and alternative (ALT-) TMM using transcriptomic signatures.Results: We have found progressive decrease of mean telomere length in all cancer subtypes compared with reference systems. Our results support the view that telomere attrition is an early event in tumorigenesis. TMM gets activated in all tumors studied due to concerted overexpression of a large fraction of genes with direct relation to telomere function, where only a very small fraction of them showed recurrent mutations. TEL-related transcriptional state was dominating in all CRC subtypes, showing, however, subtype-specific activation patterns; while contribution of the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRC and LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/or TERT genes and their interaction partners, where DKC1 is more prominent in MSS than in MSI s-CRC and can serve as a transcriptomic marker of TMM activity.Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.
Highlights
The view on telomeres has progressed from simple caps that conceal chromosome ends from DNA repair machinery [1, 2] to complex structures involving hundreds of proteins that have an active role in organizing the genome [3, 4]
Mean telomere lengths (MTL) systematically shortens in all tumor tissues of types G1 and G2 Lynch syndrome (LS-)colorectal cancer (CRC) and in microsatellite instability (MSI) and MS stable (MSS) subtypes of s-CRC compared to the respective reference mucosa samples (Figures 1A,B), which is in agreement with prior knowledge [56]
The larger differences in Lynch Syndrome (LS)-CRC and MSI s-CRC are in agreement with previous observations that link MSI and defects in mismatch repair (MMR) with higher telomere shortening rates [31]
Summary
The view on telomeres has progressed from simple caps that conceal chromosome ends from DNA repair machinery [1, 2] to complex structures involving hundreds of proteins that have an active role in organizing the genome [3, 4]. Telomeres are shortened with each cell division and trigger a DNAdamage response resulting in senescence [5]. Tumors avoid this by adding newly synthesized telomeric DNA to the chromosome ends via a telomere length maintenance mechanism (TMM), which counteracts telomere shortening and saves the tumor cells from the onset of telomeric crisis essentially contributing to cancer progression [6]. TMM gets activated via the telomerase pathway (TEL) which utilizes the telomerase ribonucleoprotein containing an RNA template for telomeric DNA synthesis [7]. Activation of telomere maintenance mechanisms (TMMs) is a hallmark of most cancers, and is required to prevent genome instability and to establish cellular immortality through reconstitution of capping of chromosome ends. Comparative studies linking tumor biology and TMM have potential impact for evaluating cancer onset and development
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