Telomere Maintenance Mechanisms in Cancer

Abstract

Tumour cells can adopt telomere maintenance mechanisms (TMMs) to avoid telomere shortening, an inevitable process due to successive cell divisions. In most tumour cells, telomere length (TL) is maintained by reactivation of telomerase, while a small part acquires immortality through the telomerase-independent alternative lengthening of telomeres (ALT) mechanism. In the last years, a great amount of data was generated, and different TMMs were reported and explained in detail, benefiting from genome-scale studies of major importance. In this review, we address seven different TMMs in tumour cells: mutations of the TERT promoter (TERTp), amplification of the genes TERT and TERC, polymorphic variants of the TERT gene and of its promoter, rearrangements of the TERT gene, epigenetic changes, ALT, and non-defined TMM (NDTMM). We gathered information from over fifty thousand patients reported in 288 papers in the last years. This wide data collection enabled us to portray, by organ/system and histotypes, the prevalence of TERTp mutations, TERT and TERC amplifications, and ALT in human tumours. Based on this information, we discuss the putative future clinical impact of the aforementioned mechanisms on the malignant transformation process in different setups, and provide insights for screening, prognosis, and patient management stratification.

Keywords: TERC; TERT; alternative lengthening of telomeres (ALT); cancer; non-defined telomere maintenance mechanism (NDTMM); promoter; telomerase; telomere; telomere maintenance mechanism (TMM).

Figure 1

Telomerase-dependent (A,B) and -independent (C) telomere maintenance mechanisms (TMM) in cancer. Telomerase reactivation depends on several mechanisms that imply modifications that can have a direct impact on TERT gene regulation, which is localized at the short arm of chromosome 5. (A) TERTp hotspot mutations (−124 bp and −146 bp upstream the ATG transcriptional start site) create binding sites for ETS transcription factors (red boxes); (B) Germline genetic variations of the TERTp and of intronic and exonic regions seem to associate with cancer risk; their genomic coordinates based on build 37 (GRCh 37, hg19/Human); (C) TERT structural variants comprise amplification and rearrangement of the gene. Hypermethylation of the TERTp or other regions, micro RNA (miRNA) regulation and post-translational histone modifications are epigenetic modifications involved in telomerase reactivation; (D) Alternative lengthening of telomeres (ALT) is a telomerase-independent mechanism that relies on the homologous recombination machinery of DNA repair to maintain telomere length. Mutation of the genes ATRX or DAXX and loss of protein expression are known events related to ALT. miRNAs and TERRA molecules are some epigenetic regulators of ALT. TERT: telomerase reverse transcriptase; TERTp: TERT promoter.

Figure 2

Frequency of telomere maintenance mechanisms in tumours by organ/anatomical site. The rates presented correspond to tumour types in which the following mechanisms were studied: TERTp mutations (TERTp mut) (orange), TERT amplification (TERT amp) (yellow), TERC amplification (TERC amp) (green), and ALT (brown). The studied population for each TMM is composed of the following cohorts (when not specified the data is depicted in Table 1, Table 2 and Table 4): Glioblastoma (GB), NOS (TERTp mut, n = 523; ALT, n = 953); oligodendroglioma (OD), NOS (TERTp mut, n = 469; ALT, n = 40); anaplastic astrocytoma (AA), NOS (TERTp mut, n = 89; ALT, n = 143); medulloblastoma (MB), NOS (TERTp mut, n = 166; TERT amp, n = 15; ALT, n = 192); hepatocellular carcinoma (HCC) (TERTp mut, n = 3091; TERT amp, n = 181; ALT, n = 121); papillary thyroid carcinoma (PTC), NOS (TERTp mut, n = 3256); pancreatic neuroendocrine tumour, NOS (pNET) (TERTp mut, n = 123; ALT, n = 849); basal cell carcinoma (BCC) (TERTp mut, n = 292); cutaneous melanoma, NOS (CM) (TERTp mut, n = 1975; TERT amp, n = 10; ALT, n = 106); acral lentiginous melanoma (ALM) (TERTp mut, n = 452; TERT amp, n = 60); myxoid liposarcoma (MLS) (TERTp mut, n = 76; ALT, n = 107); pleomorphic liposarcoma (PLS) (ALT, n = 26); leiomyosarcoma (LMS) (ALT, n = 161); gastrointestinal stromal tumour (GIST) (TERTp mut, n = 251; ALT, n = 50); muscle invasive bladder carcinoma (MIBC) (TERTp mut, n = 679; TERT amp, n = 3; ALT, n = 150); non-muscle invasive bladder carcinoma (NMIBC) (TERTp mut, n = 1682; TERT amp, n = 15); clear cell renal cell carcinoma (ccRCC) (TERTp mut, n = 443; ALT, n = 117); breast carcinoma (BRC) (TERT amp, n = 19; ALT, n = 377); oesophageal carcinoma (OEC) (TERTp mut, n = 403; TERC amp, n = 168; ALT, n = 136); non-small cell lung cancer (NSCLC) (TERTp mut, n = 961; TERT amp, n = 769; TERC amp, n = 176; ALT, n = 353). We assume for the percentage in which no defined TMM was reported that a non-defined telomere maintenance mechanisms (NDTMM) may be operating (grey).