title: Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival.
abstract: Structural compromise of the tumor suppressor gene, phosphatase and tensin homolog (PTEN), occurs in 10% of melanoma specimens, and loss of PTEN expression through DNA methylation of the PTEN promoter region has also been reported in a number of other malignancies. However, the role of PTEN promoter methylation in melanoma is not well understood. We thus sought to elucidate the prevalence of PTEN promoter methylation in melanoma specimens, its relationship to clinical features, and its impact on the outcome of patients with melanoma. PTEN promoter methylation data were acquired from an archived primary Korean melanoma cohort (KMC) of 158 patients and, for validation, 234 patients from The Cancer Genome Atlas melanoma (TCGA-MEL) cohort. Hierarchical clustering was performed to identify PTEN "high methylated" and "low methylated" samples. Subsequently, differences in clinical features and outcomes based on PTEN promoter methylation status were then analyzed using SPSS and R. In the KMC, all tumors were acquired from primary tumors and 65.7% (n = 105) were acral or mucosal by site, whereas in the TCGA-MEL cohort, 90.5% of the tumors were from regional lymph node and distant metastatic lesions. Overall, 17.7% and 45.7% of the specimens harbored BRAF mutations in the KMC and TCGA-MEL cohort, respectively. Neuroblastoma RAS viral oncogene homolog was mutated in 12.2% and 26.9% of the tumors in the KMC and TCGA-MEL cohort, respectively. In the KMC, 31 cases (19.6%) were included in the high methylated group versus 142 cases (60.7%) in the TCGA-MEL cohort (P < 0.001). Multivariate Cox-regression analysis revealed promoter methylation of PTEN to be an independent negative prognostic factor for survival in both the KMC (hazard ratio 3.76, 95% confidence interval = 1.24-11.12, P = 0.017) and TCGA-MEL cohort (HR 1.88, 95% confidence interval = 1.13-3.12, P = 0.015). Our results indicate that PTEN promoter methylation is an independent predictor for impaired survival in patients with melanoma.
authors: Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Mi Ryung
authors: MR
authors: Roh
authors: Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Sameer
authors: S
authors: Gupta
authors: Songdang Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea.
authors: Kyu-Hyun
authors: KH
authors: Park
authors: Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea.
authors: Kee Yang
authors: KY
authors: Chung
authors: Division of Oncology and Pathology, Department of Clinical Sciences, Sweden and CREATE Health Strategic Center for Translational Research, Lund University, Lund, Sweden.
authors: Martin
authors: M
authors: Lauss
authors: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors: Keith T
authors: KT
authors: Flaherty
authors: Division of Oncology and Pathology, Department of Clinical Sciences, Sweden and CREATE Health Strategic Center for Translational Research, Lund University, Lund, Sweden.
authors: Göran
authors: G
authors: Jönsson
authors: Songdang Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea; Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. Electronic address: RHA7655@yuhs.ac.
authors: Sun Young
authors: SY
authors: Rha
authors: Wellman Center for Photomedicine, Department of Dermatology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address: htsao@mgh.harvard.edu.
authors: Hensin
authors: H
authors: Tsao
mesh_terms: D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D016000:Cluster Analysis; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D008875:Middle Aged; D015999:Multivariate Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D018709:Statistics, Nonparametric; D016019:Survival Analysis
chemical_list: D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human