Dataset Information

Association of TNFRSF10D DNA-methylation with the survival of melanoma patients.

ABSTRACT: In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated in a test set using FFPE tissue samples from 32 melanoma patients. First, we identified the TNFRSF10D DNA-methylation status (TNFRSF10D methylated vs. unmethylated) as a prognostic marker for overall (p = 0.001) and for relapse-free survival (p = 0.008) in the training set. This finding was confirmed in the independent test set (n = 32; overall survival p = 0.041; relapse-free survival p = 0.012). In a multivariate Cox-regression analysis including all patients, the TNFRSF10D DNA-methylation status remained as the most significant prognostic parameter for overall and relapse-free survival (relative-risk (RR) of death, 4.6 (95% CI: 2.0-11.0; p < 0.001), RR of relapse, 7.2 (95% CI: 2.8-18.3; p < 0.001)). In this study, we demonstrate that TNFRSF10D DNA-methylation analysis of a small tissue-punch from archival FFPE melanoma tissue is a promising approach to provide prognostic information in patients with melanoma.

SUBMITTER: Ratzinger G

PROVIDER: S-EPMC4139825 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Association of TNFRSF10D DNA-methylation with the survival of melanoma patients.

Ratzinger Gudrun G Mitteregger Simone S Wolf Barbara B Berger Regina R Zelger Bernhard B Weinlich Georg G Fritsch Peter P Goebel Georg G Fiegl Heidelinde H

International journal of molecular sciences 20140707 7

In this retrospective pilot study, the DNA-methylation status of genes that have been demonstrated to be involved in melanoma carcinogenesis was analyzed in order to identify novel biomarkers for the risk assessment of melanoma patients. We analyzed DNA extracted from punch-biopsies from 68 formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Using MethyLight PCR, we examined 20 genes in specimens from a training set comprising 36 melanoma patients. Selected candidate genes were validated ...[more]

PMID: 25003639

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Project description:Importance:Melanoma treatment has been revolutionized with the development of immune-based therapies that offer durable clinical responses in a subset of patients. Clinical outcomes after treatment by immunotherapy can be influenced by the host's immune system. The immune system is modified with age by age-related immune dysfunction. Objective:To evaluate if age influences clinical outcome and immune adverse events in patients treated by immunotherapy for metastatic melanoma. Design, Setting, and Participants:This was a single-center cohort analysis in patients treated with immunotherapy for metastatic melanoma between January 2007 and February 2016, in the Lyon Sud Hospital, France. A total of 92 patients with metastatic melanoma treated with ipilimumab, nivolumab, or pembrolizumab were retrospectively analyzed. Main Outcomes and Measures:Overall survival, progression-free survival, and immune-related adverse events were evaluated for each treatment line according to the patients' age. Results:A total of 92 patients were eligible and included in this study for a total of 120 lines of treatment. Fifty-four patients were included in the cohort that was 65 years or younger (24 [44%] were female; mean [SD] age, 48.1 [12.5] years), and 38 patients were included in the cohort that was older than 65 years (12 [34%] were female; mean [SD] age, 74.8 [6.9] years). Mean follow-up duration starting at treatment initiation was 12.5 months. Patients older than 65 years treated with immunotherapy had a better mean progression-free survival (4.8 vs 3.4 months; P = .04) and overall survival (not reached vs 10.1 months; P = .009) than younger patients in univariate analysis, and after adjusting on prognosis covariates. This was particularly true with patients treated with anti-programmed cell death protein 1. Common immune-related adverse effects were similar in both cohorts. Conclusions and Relevance:Age might be associated with a better clinical outcome after treatment with immunotherapy in the real-life setting. In our cohort, older patients did not have more immune-related adverse events. Further studies are warranted to confirm our results and describe the underlying mechanisms involved.

Project description:BackgroundThe clinical course of cutaneous melanoma (CM) can differ significantly for patients with identical stages of disease, defined clinico-pathologically, and no molecular markers differentiate patients with such a diverse prognosis. This study aimed to define the prognostic value of whole genome DNA methylation profiles in stage III CM.MethodsGenome-wide methylation profiles were evaluated by the Illumina Human Methylation 27 BeadChip assay in short-term neoplastic cell cultures from 45 stage IIIC CM patients. Unsupervised K-means partitioning clustering was exploited to sort patients into 2 groups based on their methylation profiles. Methylation patterns related to the discovered groups were determined using the nearest shrunken centroid classification algorithm. The impact of genome-wide methylation patterns on overall survival (OS) was assessed using Cox regression and Kaplan-Meier analyses.ResultsUnsupervised K-means partitioning by whole genome methylation profiles identified classes with significantly different OS in stage IIIC CM patients. Patients with a "favorable" methylation profile had increased OS (P = 0.001, log-rank = 10.2) by Kaplan-Meier analysis. Median OS of stage IIIC patients with a "favorable" vs. "unfavorable" methylation profile were 31.5 and 10.4 months, respectively. The 5 year OS for stage IIIC patients with a "favorable" methylation profile was 41.2% as compared to 0% for patients with an "unfavorable" methylation profile. Among the variables examined by multivariate Cox regression analysis, classification defined by methylation profile was the only predictor of OS (Hazard Ratio = 2.41, for "unfavorable" methylation profile; 95% Confidence Interval: 1.02-5.70; P = 0.045). A 17 gene methylation signature able to correctly assign prognosis (overall error rate = 0) in stage IIIC patients on the basis of distinct methylation-defined groups was also identified.ConclusionsA discrete whole-genome methylation signature has been identified as molecular marker of prognosis for stage IIIC CM patients. Its use in daily practice is foreseeable, and promises to refine the comprehensive clinical management of stage III CM patients.

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Association of TNFRSF10D DNA-methylation with the survival of melanoma patients.

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Association of TNFRSF10D DNA-methylation with the survival of melanoma patients.

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