Telomeres play an essential role in maintaining the fidelity of chromosome ends during replication, but without an active telomere maintenance mechanism, their length decreases with each successive cell division. Aberrant telomere biology is a critical component of tumorigenesis. Replicative immortality is a hallmark of cancer and tumor cells circumvent cellular crisis associated with telomere shortening via two main mechanisms, activation of telomerase or the alternative lengthening of telomeres process (ALT). Targeted-resequencing, such as whole exome sequencing (WES), is becoming a tool for molecular diagnostics and gene discovery. While WES contains mostly data from the targeted region, a significant amount of off-target reads are not utilized for analysis. These off-target sequences likely contain additional information from the patients' genome that may be analyzed as well. Telomeric repeats, in general, are not targeted in WES, however due to their high abundance, they are present in the off-target fraction. We developed an algorithm that can estimate relative telomere length (RTL) using off-target reads from targeted-resequencing data. For proof-of-principle, we used the WES data for 14 osteosarcoma cell lines. RTL values calculated demonstrate correlations between lower RTL values in samples with hTERT expression and higher values in ALT positive cell lines, consistent with the known association of ALT and longer telomeres. In order to validate the algorithm's robustness, we evaluated published WES data for the NCI-60 panel of cell lines. The results suggest that most cells display the classic telomere shortening, while a few cell lines, such as LOX-IMVI, have long telomeres. These results will be compared to alternative techniques for measuring telomere length. In summary, we believe that this approach will enable utilization of otherwise overlooked off-target data generated by targeted-resequencing based molecular diagnostic tests.

Citation Format: Ogan D. Abaan, Joshua Waterfall, Sean Davis, Daniel Edelman, Allison Gomez, Sharon Savage, Yves Pommier, Paul Meltzer. Harvesting knowledge from unexploited genomic data: Estimating relative telomere length from targeted-resequencing. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4167. doi:10.1158/1538-7445.AM2014-4167