Comparative methylome analysis in solid tumors reveals aberrant methylation at chromosome 6p in nasopharyngeal carcinoma

Abstract

Altered patterns of DNA methylation are key features of cancer. Nasopharyngeal carcinoma (NPC) has the highest incidence in Southern China. Aberrant methylation at the promoter region of tumor suppressors is frequently reported in NPC; however, genome-wide methylation changes have not been comprehensively investigated. Therefore, we systematically analyzed methylome data in 25 primary NPC tumors and nontumor counterparts using a high-throughput approach with the Illumina HumanMethylation450 BeadChip. Comparatively, we examined the methylome data of 11 types of solid tumors collected by The Cancer Genome Atlas (TCGA). In NPC, the hypermethylation pattern was more dominant than hypomethylation and the majority of de novo methylated loci were within or close to CpG islands in tumors. The comparative methylome analysis reveals hypermethylation at chromosome 6p21.3 frequently occurred in NPC (false discovery rate; FDR=1.33 × 10−9), but was less obvious in other types of solid tumors except for prostate and Epstein–Barr virus (EBV)-positive gastric cancer (FDR<10−3). Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort. Evident enrichment of the repressive mark H3K27me3 and active mark H3K4me3 derived from human embryonic stem cells were found at these regions, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation in NPC. Our study highlights the importance of epigenetic deregulation in NPC. Polycomb Complex 2 (PRC2), responsible for H3K27 trimethylation, is a promising therapeutic target. A key genomic region on 6p with aberrant methylation was identified. This region contains several important genes having potential use as biomarkers for NPC detection.

Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma

“…Significant increase of methylation at CGI 2 was detected in 44-56% of the tumors (n = 25) (Fig. 4B) (25). These results suggested that MST1R expression may be deregulated by copy number and/or methylation changes in NPC.…”

Multiple Structural and Epigenetic Defects in the Human Leukocyte Antigen Class I Antigen Presentation Pathway in a Recurrent Metastatic Melanoma Following Immunotherapy

“…Recent studies have begun to determine the level of methylation at each CpG in the HLA gene loci in a variety of tumors (41,42). Using pyrosequencing, we quantified methylation at all the CpG sites individually in the HLA-A3 proximal promoter in COPA-159 cells and found that they were not equally susceptible to demethylation treatment; specifically, those close to site-␣ and the TATA box were demethylated to a greater extent than other sites.…”

Epstein–Barr virus: a master epigenetic manipulator

“…EBV-positive NPC and GC tumors show a unique profile of frequently DNA hypermethylated genes, sharing some common gene targets [77]. Chromosome 6p21.3 was DNA methylated in both EBV-positive NPC and EBV-positive GC, potentially serving as an epigenetic signature of EBV infection [71,77]. Chromatin modifications are also altered in NPC, with high levels of H3K27me3 and EZH2 observed [78,79].…”

“…Chromatin modifications are also altered in NPC, with high levels of H3K27me3 and EZH2 observed [78,79]. An overlap between DNA hypermethylation and the bivalent marks H3K27me3 and H3K4me3 was also observed on chromosome 6, indicating epigenetic deregulation in NPC involves both DNA methylation and histone modifications [71]. …”