The Intricate Relationship Between H3K27 Trimethylation and Merkel Cell Polyomavirus Status in Merkel Cell Carcinoma

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To the Editor: In recent years, significant progress has been made in understanding the biology of Merkel cell carcinoma (MCC), a rare cutaneous neuroendocrine neoplasm. The detection of the association between Merkel cell polyomavirus (MCPyV) and MCC, with the virus being present in the majority of tumors, has provided critical insights into MCC biology.1 High-throughput molecular sequencing techniques have shown that MCC represents a unifying phenotype derived from diverse molecular and pathogenic processes, including virus-mediated and ultraviolet radiation–driven oncogenesis.2 Despite these substantial advancements, our understanding of the entire spectrum of tumorigenesis in MCC remains to be fully elucidated, particularly focusing on the contribution of epigenetic factors to the development and progression of this malignancy. H3K27 trimethylation (H3K27me3) is a well-known epigenetic gene silencer that can inhibit transcription. This histone modification involves the trimethylation of lysine 27 on the histone H3 protein, and its association with the downregulation of gene expression is due to the recruitment of chromatin regulators by transcription factors. The polycomb repressive complex 2 (PRC2) mediates this trimethylation through its histone methyltransferase activity. Perhaps, the most well-studied expression is the loss of H3K27me3 in malignant peripheral nerve sheath tumors, but other neoplasms can also show loss of expression or a heterogeneous mosaic pattern of expression.3 Although H3K27me3 status in MCC has been investigated in several independent studies, the results have been inconsistent, leading to unclear or even contradictory findings.4–7 In this pilot study, we investigated H3K27me3 expression in a small series of well-characterized MCC with the goal of better establishing the relationship of H3K27me3 expression to MCPyV status. Formalin-fixed, paraffin-embedded sections from 31 MCC were retrieved from our archives and examined by H3K27me3 immunohistochemistry. The proportion of tumor cells showing nuclear staining was semiquantitatively recorded as “loss” (<5%), “partial loss” (≥5 and <75%), and “retained” (≥75%). Three reviewers scored these slides, and cases in which there were discrepancies were reviewed again. Clinical and follow-up information was also obtained from chart review. Our cohort of 31 MCC cases was composed predominantly of male patients (82%) with a median age of 74 years. The majority of cases (97%) have a pure rather than combined morphology (with squamous cell carcinoma in situ). Overall, 18 of 31 MCC (58%) showed loss of H3K27me3 staining (complete loss: 14 and partial loss: 4) (Figs. 1A,E). There was a significant loss of H3K27me3 staining in MCPyV-negative MCC (P = 0.03) (Fig. 1F). In addition, we also found several interesting findings. For H3K27me3-retained MCC, the median patient age was younger (65 vs. 77 years). Although 5-year estimated overall survival was significantly improved in MCPyV-positive MCC (P = 0.02), no correlation with the outcome was seen for other clinicopathologic findings, including H3K27me3 status. All cases with a combined morphology were MCPyV negative and exhibited complete loss of H3K27me3 staining.FIGURE 1.: MCC (A) demonstrating strong and diffuse staining for CM2B4 (B), a monoclonal antibody detecting MCPyV large T antigen. Complete loss of H3K27me3 nuclear staining in MCPyV-positive MCC (C). MCC with SCCIS (D) showing a complete loss of H3K27me3 (E). H3K27me3 status in MCPyV-positive and MCPyV-negative MCC cases (P = 0.03) (F).In keeping with the existing literature, our study confirms the favorable prognosis associated with MCPyV-positive tumors compared with MCPyV-negative tumors.8 The inclusion of MCPyV status in the International Collaboration on Cancer Reporting guidelines emphasizes its significance. Immunotherapy has emerged as an alternative to traditional chemotherapy for treating various solid tumors. PD-1/PD-L1 inhibitors have shown promise as primary treatments for chemotherapy-resistant and metastatic MCC cases.2 However, the advent of new immunotherapies has demonstrated efficacy and resistance against MCC, irrespective of MCPyV status, underscoring the evolving landscape of MCC therapeutics and the continued significance of MCPyV status as a prognostic factor. Our findings and those of previous studies have provided valuable insights into the role of H3K27me3 in MCC. In our cohort, we found that a significant proportion of MCC cases exhibited a loss of H3K27me3 protein expression, particularly in MCPyV-negative MCC. This reduction in H3K27me3 levels has been associated with virus-positive status in a study by Busam et al,4 whereas other investigators have reported conflicting results.5,7 In addition, recent research has shown that the global loss of H3K27me3 in both virus-positive and virus-negative MCC cases is mediated by the overexpression of EZHIP, a protein that inhibits the PRC2 complex.9 Furthermore, this inhibition of PRC2 activity, leading to decreased H3K27me3 levels, has been implicated in the development of virus-negative tumors.6,7 Our observations of an overall decrease in H3K27me3 in MCC align with these previous findings. Interestingly, in contrast to the initial findings reported by Busam et al,4 our study also reveals the loss of H3K27me3 expression in all MCPyV-negative MCC cases with combined morphology, consistent with a recent study by Durand et al.7 These divergent results highlight the intricate nature of H3K27me3-mediated epigenetic regulation and its impact on MCC tumorigenesis. Due to the complexity and observed variability of H3K27me3 status in MCC, additional studies are imperative to unravel the precise role of this epigenetic marker and its associated regulatory mechanisms in tumor progression. Larger cohorts and more nuanced investigations are required to reconcile conflicting findings and improve our understanding of MCC. The potential development of targeted treatments also necessitates a deeper comprehension of these mechanisms. These preliminary observations lay the foundation for future investigations, underscoring the significance of sustained research in this rare cutaneous tumor.

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