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

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