Prognostic and Clinicopathological Significance of Telomerase Reverse Transcriptase Upregulation in Oral Cancer: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Hanahan and Weinberg proposed to the scientific community a series of distinctive characteristics that all malignant neoplastic cells should possess, which had an enormous impact on the scientific community. One of the most relevant hallmarks of cancer involves the ability of tumor cells to acquire replicative immortality, achieved essentially through the maintenance of telomere length, dependent essentially on telomerase activity. Telomerase lengthens telomeres through the reverse transcription of a 6-bp telomere repeat sequence at the 3′ end of the telomere, which requires the enzymatic component of telomerase, i.e., the telomerase reverse transcriptase (TERT). This mechanism is essential for tumor cells to survive for a long time, and, as has been pointed out, it is frequently activated in malignant cells. This is the first systematic review and meta-analysis, based on 21 studies and 1698 oral squamous cell carcinoma (OSCC) patients, demonstrating that TERT protein overexpression behaves as a prognostic biomarker, significantly associated with poor survival in oral cancer. ABSTRACT: The aim of this systematic review and meta-analysis was to evaluate the current evidence on the prognostic and clinicopathological significance value of telomerase reverse transcriptase (TERT) upregulation in patients with oral squamous cell carcinoma (OSCC). PubMed, Embase, Web of Science, and Scopus were searched for studies published before April 2022, not restricted by date or publication language. The methodological quality of primary-level studies was critically assessed using the Quality in Prognosis Studies (QUIPS) tool. We carried out meta-analyses, explored heterogeneity and its sources, and performed subgroup, meta-regression, sensitivity, and small-study effects analyses. Twenty-one studies (1698 patients) met inclusion criteria. TERT protein overexpression was significantly associated with worse overall survival (hazard ratio [HR] = 3.01, 95% CI = 1.70–5.35, p < 0.001), disease-free survival (HR = 4.03, 95% CI = 1.80–9.05, p = 0.001), and higher histological grade OSCC (odds ratio [OR] = 3.20, 95% CI = 1.83–5.62, p < 0.001). These large effect sizes were consistently obtained by homogeneous subgroups (p > 0.10, I(2) = 0.0, respectively), which reflects a high quality of evidence. On the other hand, TERT gene mutations obtained constantly nonsignificant null effect sizes for all outcomes investigated, evidencing no prognostic or clinicopathological value. In conclusion, our findings indicate that TERT upregulation is a prognostic indicator of poor survival in oral cancer. Our findings support the immunohistochemical assessment of TERT overexpression, which could probably be incorporated into the prognostic evaluation of OSCC.