1185 DNA hypermethylation of MHC class-I genes is associated with reduced expression and survival in melanoma

Abstract

The aim of this study is to determine the role of DNA methylation in regulating expression of MHC class-I associated genes in melanoma. Reduced MHC class-I expression on the tumor cell surface is an important mechanism of escaping immunosurveillance, and is commonly seen in melanoma. DNA methylation is an epigenetic change that can silence gene expression, and has been implicated in regulating antigen expression and recognition in several cancer types. Abnormal DNA methylation is nearly universal in melanoma, however its role in regulating MHC molecule expression in melanoma is largely unknown. In this study, we investigated the methylation of MHC class-I associated molecules in melanoma tumors from The Cancer Genome Atlas. We uncovered that DNA hypermethylation of MHC class-I genes is a frequent event in melanoma, that hypermethylation is significantly associated with reduced gene expression, and identify the key CpG loci regulating expression. We found that methylation of beta-2 Microglobulin (B-2M) and HLA-B, in particular, may play important roles in melanoma survival. Patients with hypermethylation of B-2M exhibited a twofold decrease in median overall survival (HR =1.73, p=0.0001, Log-rank test). Hypermethylation of HLA-B was associated with significantly decreased 5-year overall survival (48% vs 68%, HR=1.68, p=0.0001, Log-rank test). Univariate and multivariate Cox proportional hazard analysis showed that DNA methylation of B-2M (p=5.8e-8) and HLA-B (p=5.15e-5) are prognostic factors of melanoma overall survival, independent of pathologic stage, age, gender, ulceration or Breslow thickness. Our results suggest that DNA hypermethylation may silence MHC class-I expression, and negatively impact melanoma survival. Based on our findings, targeting DNA methylation of B-2M and HLA-B may be a therapeutic strategy to restore expression of HLA class-I molecules, and potentially achieve improved immune responses in melanoma.