Intron 4–5 hTERT DNA Hypermethylation in Merkel Cell Carcinoma: Frequency, Association with Other Clinico-pathological Features and Prognostic Relevance

Abstract

Merkel cell carcinoma (MCC) is an aggressive skin tumor with neuroendocrine differentiation, mainly affecting elderly population or immunocompromised individuals. As methylation of the human telomerase reverse transcriptase (mhTERT) has been shown to be a prognostic factor in different tumors, we investigated its role in MCC, in particular in intron 4–5 where rs10069690 has been mapped and recognized as a cancer susceptibility locus. DNA methylation analysis of hTERT gene was assessed retrospectively in a cohort of 69 MCC patients from the University of Bologna, University of Turin and University of Insubria. Overall mortality was evaluated with Kaplan-Meier curves and multivariable Royston-Parmar models. High levels of mhTERT (mhTERThigh) (HR = 2.500, p = 0.015) and p63 (HR = 2.659, p = 0.016) were the only two clinico-pathological features significantly associated with a higher overall mortality at the multivariate analysis. We did not find different levels of mhTERT between MCPyV (+) and (−) cases (21 vs 14, p = 0.554); furthermore, mhTERThigh was strongly associated with older age (80.5 vs 72 years, p = 0.026), no angioinvasion (40.7% vs 71.0%, p = 0.015), lower Ki67 (50 vs 70%, p = 0.005), and PD-L1 expressions in both tumor (0 vs 3%, p = 0.021) and immune cells (0 vs 10%, p = 0.002). mhTERT is a frequently involved epigenetic mechanism and a relevant prognostic factor in MCC. In addition, it belongs to the shared oncogenic pathways of MCC (MCPyV and UV-radiations) and it could be crucial, together with other epigenetic and genetic mechanisms as gene amplification, in determining the final levels of hTERT mRNA and telomerase activity in these patients.

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…However, no significant correlation between viral infection and hypermethylation was observed, indicating that MCPyV infection may not induce DNA hypermethylation of these promoters [88]. Hypermethylation of the promoters of the RASSF2, RASSF5A, RASSF5C and RASSF10 and the TERT gene (encoding telomerase reverse transcriptase) was frequently detected in MCCs compared to normal skin samples, but again no correlation with MCPyV infection was found [89,90]. The promoter of the RB1 gene (encoding retinoblastoma protein pRb) was hypermethylated in MCCs compared to normal skin samples, but the pattern of hypermethylation of the RB1 promoter was similar in all MCCs independent of the MCPyV status [91].…”

The Prognostic Value of Proliferative Activity in Cutaneous Melanoma: A Pilot Study Evaluating the Mitotic Rate and Ki67 Index to Predict Patient Outcomes

“…Biomedicines 2024, 12, 1318 2 of 16 An immunohistochemical analysis is a widely used method in evaluating cutaneous melanocytic neoplasms, particularly for diagnosing undifferentiated or dedifferentiated tumors or for distinguishing between severely dysplastic nevi and melanomas. Nevertheless, an immunohistochemical analysis has a limited prognostic value in such cases [8][9][10].…”

“…Additionally, Ki67 has been shown to be more useful than mitotic counts for predicting prognosis in Merkel cell carcinomas [ 14 ]. Nevertheless, despite having promising results, the predictive significance depends on the adopted cut-off value, and it therefore varies based on the study [ 15 , 16 , 17 ]. Similarly, the predictive value of this parameter is uncertain in the case of cutaneous melanomas [ 18 , 19 , 20 , 21 ].…”

Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression

“…In the last years, however, further clinical and morphological features, such as sex and age, immunosuppression, as well as tumor-infiltrating lymphocytes (TILs) and tumor thickness, have been investigated in their prognostic value [15][16][17][18][19]. In addition, cKIT, PDGFRA, ALK and EGFR represent only some of the biomarkers examined in MCC in order to better define its pathogenesis [20][21][22][23][24][25]. In particular, ALK tumor expression has been reported in MCC and was recently shown to correlate with viral status as well as a longer survival [20,22,26].…”