TelomereHunter – in silico estimation of telomere content and composition from cancer genomes

Abstract

Background Establishment of telomere maintenance mechanisms is a universal step in tumor development to achieve replicative immortality. These processes leave molecular footprints in cancer genomes in the form of altered telomere content and aberrations in telomere composition. To retrieve these telomere characteristics from high-throughput sequencing data the available computational approaches need to be extended and optimized to fully exploit the information provided by large scale cancer genome data sets. Results We here present TelomereHunter, a software for the detailed characterization of telomere maintenance mechanism footprints in the genome. The tool is implemented for the analysis of large cancer genome cohorts and provides a variety of diagnostic diagrams as well as machine-readable output for subsequent analysis. A novel key feature is the extraction of singleton telomere variant repeats, which improves the identification and subclassification of the alternative lengthening of telomeres phenotype. We find that whole genome sequencing-derived telomere content estimates strongly correlate with telomere qPCR measurements (r = 0.94). For the first time, we determine the correlation of in silico telomere content quantification from whole genome sequencing and whole genome bisulfite sequencing data derived from the same tumor sample (r = 0.78). An analogous comparison of whole exome sequencing data and whole genome sequencing data measured slightly lower correlation (r = 0.79). However, this is considerably improved by normalization with matched controls (r = 0.91). Conclusions TelomereHunter provides new functionality for the analysis of the footprints of telomere maintenance mechanisms in cancer genomes. Besides whole genome sequencing, whole exome sequencing and whole genome bisulfite sequencing are suited for in silico telomere content quantification, especially if matched control samples are available. The software runs under a GPL license and is available at https://www.dkfz.de/en/applied-bioinformatics/telomerehunter/telomerehunter.html . Electronic supplementary material The online version of this article (10.1186/s12859-019-2851-0) contains supplementary material, which is available to authorized users.

Genomic footprints of activated telomere maintenance mechanisms in cancer

“…Telomere read extraction and computational telomere content estimation. The telomere content of WGS samples was determined using the software tool TelomereHunter 64 . In short, telomeric reads containing six nonconsecutive instances of the four most common telomeric repeat types (TTAGGG, TCAGGG, TGAGGG, and TTGGGG) were extracted.…”

Telomeres reforged with non-telomeric sequences in mouse embryonic stem cells

“…Accessibility of telomeric repeats was quantified from ATAC-seq FASTQ file using Computel (version 1.2) with default parameters. Variant telomere content was determined by TelomereHunter (version 1.1.0) with default parameters 64 . Pair and Single telomere-containing reads was counted by Telomerecat (version 3.2) with default parameters 65 .…”

Elevated somatic mutation burdens in normal human cells due to defective DNA polymerases

“…Results of the algorithm based on sequencing data generated by the Illumina X10 and other sequencing platforms does not demonstrate this pattern and can be relied upon. For this analysis we favoured TelomereHunter which is well established method used in tumour sequencing analyses 68 , shows good concordance with other methods of telomere length estimation 69 and is reliable across all tested samples sequenced on the Illumina NovaSeq platform.…”