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

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

doi:10.1016/j.prp.2021.153689

Cited by 2 publications

(3 citation statements)

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“…24 DNA methylation of these genes has been described to be associated with gene expression and survival in various malignancies. [25][26][27][28][29][30][31][32][33][34][35][36][37][38] The pivotal involvement of BAP1-associated methylation repatterning in uveal melanomagenesis and progression, survival, immunosuppression, and differential expression of immune checkpoint genes prompted us to investigate the DNA methylation landscape of immune checkpoint genes with regard to transcriptional activity, BAP1-mutation status, and clinical outcomes in UM. We focused on the immune checkpoint genes CTLA4, PD-1, PD-L1, PD-L2 (PD-1 ligand 2, encoded by the PDCD1LG2 gene), LAG3, TIGIT (T-cell immunoreceptor with Ig and ITIM domains), and HAVCR2 (hepatitis A virus cellular receptor 2, also known as TIM-3 and TIM3), which are targets of either approved or clinically tested immune checkpoint inhibitors.…”

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confidence: 99%

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CTLA4, PD-1, PD-L1, PD-L2, TIM-3, TIGIT, and LAG3 DNA Methylation Is Associated With BAP1-Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma

Vos¹,

Cano²,

Zarbl³

et al. 2022

Journal of Immunotherapy

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Uveal melanoma (UM) is an aggressive disease with poor response to oncological treatment, including immunotherapy. Loss of the epigenetic modifier BRCA1-associated protein 1 (BAP1) function drives UM oncogenesis and is associated with an immune-suppressive tumor microenvironment, poor prognosis, and a distinct DNA methylation and gene expression profile. Our study aimed to analyze comprehensively the DNA methylation status of the immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA4, TIM-3 (HAVCR2), TIGIT, and LAG3 and its association with mRNA expression, BAP1-aberrancy, and patients' survival. We analyzed the DNA methylation landscape of immune checkpoint genes at single CpG resolution in N = 80 UM samples provided by The Cancer Genome Atlas. We analyzed CpG methylation levels of the immune checkpoints with regard to their transcriptional signatures and patient outcomes.Methylation of specific CpG sites within the immune checkpoint genes PD-1, PD-L1, PD-L2, CTLA4, TIM-3, TIGIT, and LAG3 correlated strongly with mRNA expression levels, indicating a strong regulation of gene expression through DNA methylation. Moreover, immune checkpoint gene methylation was strongly associated with BAP1-mutation status and associated with overall survival in UM. Our data indicate an epigenetic regulation of immune checkpoints through DNA methylation in UM. Further, our data highlight the prognostic significance of DNA methylation of immune checkpoint genes in UM thereby providing a rationale for methylation testing as predictive biomarkers for immunotherapy response.

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confidence: 99%

“…BAP1 -aberrant tumors express higher mRNA levels of several immune checkpoints including PD-1, PD-1 ligand 1 (PD-L1, encoded by the CD274 gene), CTLA-4, and lymphocyte activating 3 (LAG3, encoded by the LAG3 gene) 24. DNA methylation of these genes has been described to be associated with gene expression and survival in various malignancies 25–38…”

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confidence: 99%

CTLA4, PD-1, PD-L1, PD-L2, TIM-3, TIGIT, and LAG3 DNA Methylation Is Associated With BAP1-Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma

Vos¹,

Cano²,

Zarbl³

et al. 2022

Journal of Immunotherapy

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“…The deletion of CDKN2A is a frequent event driving melanoma progression. ranging from 40 to 70% of melanoma cases [80,81].…”

Section: Aberrant Cdk4-prb Pathway Signaling Pathways In MMmentioning

confidence: 99%

Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of mucosal melanoma

Shi,

Ju,

et al. 2024

Holist Integ Oncol

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Mucosal melanoma (MM) is a rare and aggressive form of melanoma with a poorer prognosis compared to other subtypes. Recent large-scale next-generation sequencing studies, including our own research, have demonstrated that the molecular characteristics and potential oncogenic drivers of MM differ significantly from those of cutaneous melanoma. The emergence of selective CDK4/6 inhibitors, already approved for use in breast cancer and undergoing phase III clinical trials for other solid tumors, represents a promising development in the treatment of MM. Recent studies have shown that CDK4/6 inhibitors not only induce cell cycle arrest but also play a crucial role in facilitating the interaction between tumor cells and the host immune system. Moreover, our findings indicate that dysregulation of cell cycle progression due to cyclin‐dependent kinase 4 (CDK4) amplification is a significant genetic characteristic in a substantial portion of MM cases. Targeting CDK4 in specific MM patients shows promise for precision cancer therapy, utilizing molecularly characterized MM patient-derived xenograft (PDX) models and clinical trials. This paper provides an overview of existing literature on CDK4/6 dysregulation in MM, as well as preclinical and clinical investigations on CDK4/6 inhibitors and potential combination therapies for MM treatment.

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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

Cited by 2 publications

References 37 publications

CTLA4, PD-1, PD-L1, PD-L2, TIM-3, TIGIT, and LAG3 DNA Methylation Is Associated With BAP1-Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma

CTLA4, PD-1, PD-L1, PD-L2, TIM-3, TIGIT, and LAG3 DNA Methylation Is Associated With BAP1-Aberrancy, Transcriptional Activity, and Overall Survival in Uveal Melanoma

Potential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of mucosal melanoma

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