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

Costantino Ricci, Luca Morandi, Alberto Righi, Dino Gibertoni, Francesca Maletta, Francesca Ambrosi, Claudio Agostinelli, Silvia Uccella, Silvia Asioli, Fausto Sessa, Maria Pellilli, Roberta Maragliano, Stefano La Rosa, Mauro Giulio Papotti, Sofia Asioli

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalModern Pathology
DOIs
Publication statusE-pub ahead of print - Apr 11 2019

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Merkel Cell Carcinoma
Methylation
Programmed Cell Death 1 Receptor
Merkel cell polyomavirus
Multivariate Analysis
Neuroendocrine Tumors
Mortality
Proportional Hazards Models
Neoplasms
Skin

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PD-1 (PDCD1) promoter methylation in Merkel cell carcinoma: prognostic relevance and relationship with clinico-pathological parameters. / Ricci, Costantino; Morandi, Luca; Righi, Alberto; Gibertoni, Dino; Maletta, Francesca; Ambrosi, Francesca; Agostinelli, Claudio; Uccella, Silvia; Asioli, Silvia; Sessa, Fausto; Pellilli, Maria; Maragliano, Roberta; La Rosa, Stefano; Papotti, Mauro Giulio; Asioli, Sofia.

In: Modern Pathology, 11.04.2019.

Research output: Contribution to journalArticle

Ricci, C, Morandi, L, Righi, A, Gibertoni, D, Maletta, F, Ambrosi, F, Agostinelli, C, Uccella, S, Asioli, S, Sessa, F, Pellilli, M, Maragliano, R, La Rosa, S, Papotti, MG & Asioli, S 2019, 'PD-1 (PDCD1) promoter methylation in Merkel cell carcinoma: prognostic relevance and relationship with clinico-pathological parameters', Modern Pathology. https://doi.org/10.1038/s41379-019-0261-5
Ricci, Costantino ; Morandi, Luca ; Righi, Alberto ; Gibertoni, Dino ; Maletta, Francesca ; Ambrosi, Francesca ; Agostinelli, Claudio ; Uccella, Silvia ; Asioli, Silvia ; Sessa, Fausto ; Pellilli, Maria ; Maragliano, Roberta ; La Rosa, Stefano ; Papotti, Mauro Giulio ; Asioli, Sofia. / PD-1 (PDCD1) promoter methylation in Merkel cell carcinoma: prognostic relevance and relationship with clinico-pathological parameters. In: Modern Pathology. 2019.
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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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T1 - PD-1 (PDCD1) promoter methylation in Merkel cell carcinoma: prognostic relevance and relationship with clinico-pathological parameters

AU - Ricci, Costantino

AU - Morandi, Luca

AU - Righi, Alberto

AU - Gibertoni, Dino

AU - Maletta, Francesca

AU - Ambrosi, Francesca

AU - Agostinelli, Claudio

AU - Uccella, Silvia

AU - Asioli, Silvia

AU - Sessa, Fausto

AU - Pellilli, Maria

AU - Maragliano, Roberta

AU - La Rosa, Stefano

AU - Papotti, Mauro Giulio

AU - Asioli, Sofia

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AB - 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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