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.

The chromosomal instability 25 gene signature is identified in clear cell renal cell carcinoma and serves as a predictor for survival and Sunitinib response

“…As shown in Figure 4B , TERT mRNA levels were significantly higher coupled with the increased frequency of TERT copy number gain in CIN25-C2 tumors (C2 vs C1 for TERT mRNA and copies: P = 1.84E-08, and 0.018, respectively). Telomerase activity, as determined using telomerase score ( 38 ), increased markedly in the CIN25-C2 tumors compared with that in CIN25-C1 tumors ( P = 2.15E-05) ( Figure 4C ). Moreover, there was a significantly positive correlation between telomerase and CIN25 ssGSEA scores ( R = 0.43, P < 2.22E-16) ( Figure 4C ).…”

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…Telomerase enzyme is a ribonucleoprotein complex with a molecular weight of approximately 500 kDa (gel filtration-based estimate), however, its core holyenzyme is only composed of telomerase reverse transcriptase (TERT), the subunit catalyzing telomeric DNA synthesis, and internal template telomerase RNA component (TERC) (9)(10)(11). TERC is ubiquitously expressed in human tissues/cells, while the TERT gene is stringently repressed in most normal human cells, which acts as the key mechanism to silence telomerase (4).…”

Dyskerin and telomerase RNA component are sex-differentially associated with outcomes and Sunitinib response in patients with clear cell renal cell carcinoma

“…One of important DKC1 targets is non-coding telomerase RNA component (TERC) that serves as an internal template for telomerase-mediated telomere elongation [ 21 , 22 ]. Telomerase is a multi-unit complex consisting of the catalytic component telomerase reverse transcriptase (TERT), TERC, DKC1, and others [ 23 ]. DKC1 deficiency induces diminished TERC expression and telomerase activity, thereby leading to telomere shortening and subsequent telomere pathologies [ 21 , 24 , 25 ].…”

“…For instance, telomerase confers resistance to FLT3 inhibitors in leukemic cells [ 29 ]. DKC1 as one of key telomerase components is overexpressed in many types of cancer [ 23 , 32 – 41 ]. Moreover, DKC1 also exhibits other biological activities, including regulation of ribosome biogenesis and splicing events [ 20 , 21 , 33 , 38 , 39 ].…”

“…Moreover, DKC1 also exhibits other biological activities, including regulation of ribosome biogenesis and splicing events [ 20 , 21 , 33 , 38 , 39 ]. Interestingly, DKC1 has been shown as a prognostic factor in ccRCC and higher DKC1 expression is associated with significantly shorter patient survival [ 23 , 32 ].…”