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PD-1 (PDCD1) promoter methylation in Merkel cell carcinoma: prognostic relevance and relationship with clinico-pathological parameters

Abstract

Merkel cell carcinoma is an aggressive neuroendocrine skin tumor, for which several non-conclusive prognostic factors of adverse clinical behavior have been reported. As promoter methylation of the immune checkpoint receptor CD279/PD-1/PDCD1(mPDCD1) has been shown to be a prognostic factor in different cancers, we investigated its role in Merkel cell carcinoma. mPDCD1was assessed retrospectively in a cohort of 69 Merkel cell carcinoma patients from the University of Bologna, University of Turin and University of Insubria. Kaplan-Meier curves and log-rank tests were calculated for all variables. To assess the influence of mPDCD1, the Cox proportional hazards model and different Royston-Parmar models were evaluated. High PDCD1 methylation (mPDCD1high) was associated with a higher overall mortality at both the univariate analysis (log rank test: χ2 = 5.17, p = 0.023; permutation test: p = 0.023) and the multivariate analysis (HR = 2.111, p = 0.042). The other variables associated with a higher overall mortality at the multivariate analysis were clinical stage III-IV (HR = 2.357, p = 0.008), size > 2 cm (HR = 2.248, p = 0.031) and Merkel cell polyomavirus (HR = 0.397, p = 0.015). Further, mPDCD1high was strongly associated with older age (81 vs 76 years, p = 0.042), absence of immune cells (92.6%, p < 0.001), no expression of PD-L1 by immune cells (70.4%, p = 0.041) and by both immune and tumor cells (70.4%, p = 0.001). mPDCD1 is a valid prognostic parameter in patients affected by Merkel cell carcinoma. In addition, it could provide an estimate of the global PD-1/PD-L1 expression with potentially relevant implications from a therapeutic point of view.

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This work will be partially presented as a Poster Session at the 108th Meeting of the United States and Canadian Academy of Pathology in National Harbor, Maryland, 16-21 March 2019

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Acknowledgements

This work was supported by Ricerca Fondamentale Orientata (RFO) to Dr. Sofia Asioli, University of Bologna, Italy.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics statement

All clinical investigations were conducted according to the principles of the Declaration of Helsinki. The study was approved by the Institutional Review Board and the local ethics committee (study number CE18083, DIBINEM-UNIBO-rif. CE AVEC number 377/2018/OSS/AUSLBO). All information regarding the human material used in this study was managed using anonymous numerical codes.

Correspondence to Sofia Asioli.

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