The role of 5-hydroxymethylcytosine in melanoma

Li, Fengjuan; Li, Liming; Zhang, Ruihua; Cui, Xu; Zhou, Pan; Long, Jia; Hu, Gang; Jiang, Mingjun

doi:10.1097/cmr.0000000000000349

Cited by 10 publications

(3 citation statements)

References 38 publications

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“…In addition to the study by Lian CG et al, 5-hmC expression has been evaluated in several studies in cutaneous melanocytic proliferations [ 15 , 16 , 17 ]. Our results are in line with these studies, which showed a significant loss of 5-hmC in melanomas compared to nevi [ 18 ]. In the study by Larson AR et al [ 15 ], 5-hmC loss was evaluated by immunohistochemistry in a group of 175 cases including 18 benign cutaneous nevi, 20 dysplastic nevi, 10 atypical Spitz nevi, 20 borderline tumors, 5 cutaneous melanomas developing from nevi and 102 primary cutaneous melanomas.…”

Section: Discussionsupporting

confidence: 93%

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma

et al. 2021

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Aims: Conjunctival and cutaneous melanoma partially share similar clinical and molecular backgrounds. As 5-hydroxymethylcytosine (5-hmC) loss has been demonstrated in cutaneous melanoma, we decided to assess if similar changes were occurring in conjunctival melanoma. Methods: 5-methylcytosine (5-mC), 5-hmC and TET2 were respectively identified by immunohistochemistry and RNA ISH in 40 conjunctival nevi and 37 conjunctival melanomas. Clinicopathological correlations were established. Results: 5-mC, TET2 and 5-hmC were respectively identified in 67.5%, 95% and 100% of conjunctival nevi and in 81.1%, 35.1% and 54% of conjunctival melanomas. A significant 5-hmC and TET2 loss was identified in conjunctival melanoma comparing to nevus, as well as a significant correlation between TET2 and 5-hmC expression. In the melanomas, 5-hmC expression was only significantly associated with local lymphatic invasion, but not with other clinicopathological parameters. There was a correlation between TET2 expression and the localization of the tumors. 5-mC expression was not associated with any clinicopathological parameters. Conclusions: We identified a significant 5-hmC loss in conjunctival melanoma similar to cutaneous melanoma. This loss may possibly be attributed to TET2 loss or IDH1 mutations. 5-hmC loss in conjunctival melanoma may help in the differential diagnosis between atypical conjunctival nevus and conjunctival melanoma.

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Section: Discussionsupporting

confidence: 93%

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma

et al. 2021

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“…These include reduced survival rates and an increased risk of disease recurrence. Melanoma is a highly aggressive form of skin cancer, exhibiting a significant loss of 5-hmC levels at all stages of melanomas, including primary melanomas, metastases, conjunctival melanomas, mucosal melanomas, and sentinel lymph node biopsies [14]. Merely acral melanoma did not show a significant loss of expression 5-hmC.…”

Section: Introductionmentioning

confidence: 92%

Standardized Computer-Assisted Analysis of 5-hmC Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas

Koch,

Berking,

Erber

et al. 2023

IJMS

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5-Hydroxymethylcytosine (5-hmC) is an important intermediate of DNA demethylation. Hypomethylation of DNA is frequent in cancer, resulting in deregulation of 5-hmC levels in melanoma. However, the interpretation of the intensity and distribution of 5-hmC immunoreactivity is not very standardized, which makes its interpretation difficult. In this study, 5-hmC-stained histological slides of superficial spreading melanomas (SSM) and dysplastic compound nevi (DN) were digitized and analyzed using the digital pathology and image platform QuPath. Receiver operating characteristic/area under the curve (ROCAUC) and t-tests were performed. A p-value of <0.05 was used for statistical significance, and a ROCAUC score of >0.8 was considered a “good” result. In total, 92 5-hmC-stained specimens were analyzed, including 42 SSM (45.7%) and 50 DN (54.3%). The mean of 5-hmC-positive cells/mm2 for the epidermis and dermo-epidermal junction and the entire lesion differed significantly between DN and SSM (p = 0.002 and p = 0.006, respectively) and showed a trend towards higher immunoreactivity in the dermal component (p = 0.069). The ROCAUC of 5-hmC-positive cells of the epidermis and dermo-epidermal junction was 0.79, for the dermis 0.74, and for the entire lesion 0.76. These results show that the assessment of the epidermal with junctional expression of 5-hmC is slightly superior to dermal immunoreactivity in distinguishing between DN and SSM.

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“…Oncometabolite 2-HG also inhibits the function of ten-eleven translocation (TET) enzymes, which are responsible for converting 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). It competes with 2-OG for binding to the active site of 2-OG-dependent oxygenase [ 11 , 12 ] ( Fig. 1 ).…”

Section: Introductionmentioning

confidence: 99%

The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory

KURDI,

ALKHOTANI,

SABBAGH

et al. 2024

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Background The dysregulation of Isocitrate dehydrogenase (IDH) and the subsequent production of 2-Hydroxyglutrate (2HG) may alter the expression of epigenetic proteins in Grade 4 astrocytoma. The interplay mechanism between IDH, O-6-methylguanine-DNA methyltransferase ( MGMT) -promoter methylation, and protein methyltransferase proteins-5 ( PRMT5) activity, with tumor progression has never been described. Methods A retrospective cohort of 34 patients with G4 astrocytoma is classified into IDH-mutant and IDH-wildtype tumors. Both groups were tested for MGMT -promoter methylation and PRMT5 through methylation-specific and gene expression PCR analysis. Inter-cohort statistical significance was evaluated. Results Both IDH-mutant WHO grade 4 astrocytomas (n = 22, 64.7%) and IDH-wildtype glioblastomas (n = 12, 35.3%) had upregulated PRMT5 gene expression except in one case. Out of the 22 IDH-mutant tumors, 10 (45.5%) tumors showed MGMT -promoter methylation and 12 (54.5%) tumors had unmethylated MGMT . All IDH-wildtype tumors had unmethylated MGMT . There was a statistically significant relationship between MGMT -promoter methylation and IDH in G4 astrocytoma ( p -value = 0.006). Statistically significant differences in progression-free survival (PFS) were also observed among all G4 astrocytomas that expressed PRMT5 and received either temozolomide (TMZ) or TMZ plus other chemotherapies, regardless of their IDH or MGMT -methylation status ( p -value=0.0014). Specifically, IDH-mutant tumors that had upregulated PRMT5 activity and MGMT -promoter methylation, who received only TMZ, have exhibited longer PFS. Conclusions The relationship between PRMT5 , MGMT -promoter, and IDH is not tri-directional. However, accumulation of D2-hydroxyglutarate (2-HG), which partially activates 2-OG-dependent deoxygenase, may not affect their activities. In IDH-wildtype glioblastomas, the 2HG-2OG pathway is typically inactive, leading to PRMT5 upregulation. TMZ alone, compared to TMZ-plus, can increase PFS in upregulated PRMT5 tumors. Thus, using a PRMT5 inhibitor in G4 astrocytomas may help in tumor regression.

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The role of 5-hydroxymethylcytosine in melanoma

Cited by 10 publications

References 38 publications

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma

5-Hydroxymethylcytosine Loss in Conjunctival Melanoma

Standardized Computer-Assisted Analysis of 5-hmC Immunoreactivity in Dysplastic Nevi and Superficial Spreading Melanomas

The interplay mechanism between IDH mutation, MGMT-promoter methylation, and PRMT5 activity in the progression of grade 4 astrocytoma: unraveling the complex triad theory

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