Promoter Methylation of PTEN Is a Significant Prognostic Factor in Melanoma Survival

Mi Ryung Roh, Sameer Gupta, Kyu Hyun Park, Kee Yang Chung, Martin Lauss, Keith T. Flaherty, Göran Jönsson, Sun Young Rha, Hensin Tsao

Research output: Contribution to journalArticlepeer-review

32 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1002-1011
Number of pages10
JournalJournal of Investigative Dermatology
Volume136
Issue number5
DOIs
Publication statusPublished - 2016

Bibliographical note

Funding Information:
This work was made possible by a grant from the NIH (K24 CA149202 to HT), a grant from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (No. 2013R1A2A2A04015894 to MRR and KYC), a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI13C2096 to SYR), and the generous donors to the MGH Millennium Melanoma Fund and Innovations in Melanoma Care Fund.

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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