Genomic, epigenomic, and transcriptomic signatures for telomerase complex components: a pan-cancer analysis.

Abstract

Telomerase activation is required for malignant transformation. Recent advances in high-throughput technologies have enabled the generation of complex datasets, thus providing alternative approaches to exploring telomerase biology more comprehensively, which has proven to be challenging due to the need for laborious assays required to test for telomerase activity. To solve these issues, several groups have analyzed TCGA pan-cancer tumor datasets by investigating telomerase reverse transcriptase (TERT), the catalytic subunit for telomerase activity, or its surrogates. However, telomerase is a multiunit complex containing not only TERT, but also numerus cofactors required for telomerase function. Here we determined genomic and molecular alterations of 10 well-characterized telomerase components in the TCGA and CCLE datasets. We calculated a telomerase score (TS) based on their expression profiles and clustered tumors into low, high, and intermediate subtypes. To validate the in silico analysis result, we used immunoblotting and telomerase assays. High TS subtypes were significantly associated with stemness, proliferation, epithelial to mesenchymal transition, hyperactivation of oncogenic signaling pathways, shorter patient survival, and infiltration of dysfunctional T-cells or poor response to immunotherapy. Copy number alterations in 10 telomerase components were widespread and associated with the level of their expression. Surprisingly, primary tumors and cancer cell lines frequently displayed a homozygous deletion of the TCAB1 gene, encoding a telomerase protein essential for telomerase trafficking, assembling, and function, as previously reported. However, tumors or cells carrying a TCAB1 deletion still exhibited telomerase activity comparable to or even higher than their wildtype counterparts. Collectively, applying telomerase component-based TS in complex datasets provided a robust tool for telomerase analyses. Our findings also reveal a tight connection between telomerase and other oncogenic signaling pathways; TCAB1 may acts as a dispensable telomerase component. Moreover, TS may serve as a useful biomarker to predict patient outcomes and response to immunotherapy.