Revisiting Telomere Shortening in Cancer

Abstract

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

The Solo Play of TERT Promoter Mutations

“…Constitutive activation of the GFR/FGFR-BRAF/RAS pathway leads to constitutive cell growth and division [153]. Mutations in these oncogenes are often detectable in low-grade tumors and probably precede TERTp mutations [22,61,77,112]. The picture is even more clear-cut in HCC, where mutations in β-catenin (CTNNB1) neatly precede TERTp mutations during the process of malignant transformation [62,95,120].…”

“…The proliferative advantage conferred by driver mutations in these pathways leads to accelerated telomere erosion. Accordingly, most tumors display telomere dysfunction and shortened telomeres, which leads to chromosome instability [10,22,61,66,98,112,115]. In this scenario, TERT reactivation regenerates telomeres sufficiently to maintain them above the critical threshold and to stabilize the tumor genome [3,18,145].…”

“…Similarly, the region between −600 and −200 from the TSS contains a second CTCF binding site and is partially hypermethylated in TERT-expressing cells [41][42][43][44]. The transcriptional control of TERT has been comprehensively reviewed recently [3,4,9,[18][19][20][21][22]29,48] and, as such, is beyond the scope of this review. In this review, we focused on the distribution and exclusiveness of TERTp mutations.…”

“…Although TERT activity is regulated principally at the transcriptional level (reviewed in References [3,4,9,[17][18][19][20][21][22]), it may also be regulated through splicing [23,24], post-translational modifications, or intracellular trafficking [25][26][27][28]. The TERT promoter (TERTp) contains binding sites for numerous transcriptional activators including Sp-1, c-Myc, Hypoxia Induced Factor (HIF), AP-2, β-catenin, NF-κB, E-twenty-six (Ets)/ternary complex factors (TCF) family members, and transcriptional repressors (Wilms' tumor (WT1), TP53, Nuclear Transcription Factor, X-Box Binding (NFX-1), Mad-1 and CCCTC binding factor (CTCF)) [3,4,9,[17][18][19][20][21]29].…”

Need for the biobanking and all‐round “‐omics” approach for cancers of mouth/oral region

“…The current concept for biobanks for cancers of mouth/oral origin has been established by the rising demands for access to biological material from large populations, particularly upheld by the evolution of sophisticated high-throughput "-omics" technologies such as parallel DNA sequencing, array techniques and mass spectrometry, which equip detailed and affordable analyses (Okamoto & Seimiya, 2019;Xian, Duleba, Yamamoto, Vincent, & McKeon, 2018).…”