Beschreibung:
Background: Activation of telomere maintenance mechanisms (TMMs) is a hallmarkof most cancers, and is required to prevent genome instability and to establish cellularimmortality through reconstitution of capping of chromosome ends. TMM depends onthe cancer type. Comparative studies linking tumor biology and TMM have potentialimpact for evaluating cancer onset and development.Methods: We have studied alterations of telomere length, their sequence compositionand transcriptional regulation in mismatch repair deficient colorectal cancers arising inLynch syndrome (LS-CRC) and microsatellite instable (MSI) sporadic CRC (MSI s-CRC),and for comparison, in microsatellite stable (MSS) s-CRC and in benign colonmucosa. Our study applied bioinformatics analysis of whole genome DNA and RNAsequencing data and a pathway model to study telomere length alterations and thepotential effect of the “classical” telomerase (TEL-) and alternative (ALT-) TMM usingtranscriptomic signatures.Results: We have found progressive decrease of mean telomere length in allcancer subtypes compared with reference systems. Our results support the viewthat telomere attrition is an early event in tumorigenesis. TMM gets activated inall tumors studied due to concerted overexpression of a large fraction of geneswith direct relation to telomere function, where only a very small fraction of themshowed recurrent mutations. TEL-related transcriptional state was dominating in all CRCsubtypes, showing, however, subtype-specific activation patterns; while contributionof the ALT-TMM was slightly more prominent in the hypermutated MSI s-CRCand LS-CRC. TEL-TMM is mainly activated by over-expression of DKC1 and/orTERT genes and their interaction partners, where DKC1 is more prominent in MSSthan in MSI s-CRC and can serve as a transcriptomic marker of TMM activity.Conclusions: Our results suggest that transcriptional patterns are indicative for TMMpathway activation with subtle differences between TEL and ALT mechanisms in a CRCsubtype-specific fashion. Sequencing data potentially provide a suited measure to studyalterations of telomere length and of underlying transcriptional regulation. Further studiesare needed to improve this method.