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Wrede N, Hoffmann I, Vollbrecht C, et al. Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis. Pathol Res Pract. 2021;229:153689doi: 10.1016/j.prp.2021.153689.
Wrede, N., Hoffmann, I., Vollbrecht, C., Koch, I., Wolkenstein, P., Klauschen, F., Capper, D., von Laffert, M., & Jurmeister, P. (2021). Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis. Pathology, research and practice, 229153689. https://doi.org/10.1016/j.prp.2021.153689
Wrede, Niklas, et al. "Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis." Pathology, research and practice vol. 229 (2021): 153689. doi: https://doi.org/10.1016/j.prp.2021.153689
Wrede N, Hoffmann I, Vollbrecht C, Koch I, Wolkenstein P, Klauschen F, Capper D, von Laffert M, Jurmeister P. Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis. Pathol Res Pract. 2021 Nov 22;229:153689. doi: 10.1016/j.prp.2021.153689. Epub 2021 Nov 22. PMID: 34844086.
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Pathol Res Pract. 2021 Nov 22;229:153689. doi: 10.1016/j.prp.2021.153689. Epub 2021 Nov 22.

Comparative investigation of cell cycle and immunomodulatory genes in mucosal and cutaneous melanomas: Preliminary data suggest a potential promising clinical role for p16 and the PD-1/PD-L1 axis.

Pathology, research and practice

Niklas Wrede, Inga Hoffmann, Claudia Vollbrecht, Ines Koch, Peggy Wolkenstein, Frederick Klauschen, David Capper, Maximilian von Laffert, Philipp Jurmeister

Affiliations

  1. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany.
  2. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
  3. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany; Institute of Pathology, Ludwig Maximilians University Hospital Munich, Thalkirchner Str. 36, 80337 Munich, Germany.
  4. Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
  5. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany; Institute of Pathology, University Hospital Leipzig, Leipzig, Germany.
  6. Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Pathology, Berlin, Germany; Institute of Pathology, Ludwig Maximilians University Hospital Munich, Thalkirchner Str. 36, 80337 Munich, Germany. Electronic address: [email protected].

PMID: 34844086 DOI: 10.1016/j.prp.2021.153689

Abstract

Mucosal melanomas arise from the mucosal lining of various organs. Their etiology is currently unknown and there are no tissue-based methods to differentiate it from cutaneous melanomas. Furthermore, prognostic and predictive markers (e.g. for immune checkpoint inhibition) are lacking. In this study, we aimed to assess the protein expression levels of cell cycle-associated proteins and immune checkpoint markers in a cohort of mucosal melanomas in comparison to cutaneous melanomas and evaluated the effect of potential regulatory mechanisms. We performed immunohistochemistry, DNA methylation analysis and copy number profiling of 47 mucosal and 28 cutaneous melanoma samples. Protein expression of CD117, Ki67 and p16 was higher in mucosal melanomas, while BCL2, Cyclin D1, PD-1 and PD-L1 were overexpressed in cutaneous melanomas. CDKN2A deletions were the most prevalent numeric chromosomal alterations in both mucosal and cutaneous melanoma and were associated with decreased p16 expression. KIT was frequently amplified in mucosal melanomas, but not associated with CD117 expression. On the other hand, amplification of CCND1 lead to Cyclin D1 overexpression. In mucosal melanoma patients high PD-1 expression and high PD-L1 promoter methylation levels were associated with improved survival. PD-L1 expression correlated with response to immune checkpoint inhibitor therapy in the combined group of melanoma patients. Mucosal and cutaneous melanomas show different expression levels of cell cycle-associated and immunomodulatory proteins that are partially regulated by DNA methylation and copy number alterations. PD-1 expression and PD-L1 promoter methylation levels might be a prognostic marker for mucosal melanomas.

Copyright © 2021 Elsevier GmbH. All rights reserved.

Keywords: Cell-cycle regulatory proteins; Immune checkpoint proteins; Immunohistochemistry; Malignant melanoma; Mucosal tissue

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