Aberrant methylation at chromosome 6p as novel biomarkers for diagnosis and prognosis of nasopharyngeal carcinoma

Abstract

BACKGROUND: Nasopharyngeal carcinoma (NPC) has the highest incidence in Guangdong province and Hong Kong in Southern China. Early detection of NPC is necessary to improve patient survival. Although aberrant methylation at promoter region of the tumour suppressors were often reported in NPC, genome-wide methylation changes have not been comprehensively investigated. AIM: We aimed to examine the methylation profile of NPC patient tumours using a high-throughput approach to discover candidate biomarkers for early detection of NPC. METHODS: We systematically analyzed methylome data in the primary tumours and matched normal adjacent tissues from 25 NPC patients collected by Area of Excellence (AoE) NPC Tissue Bank using the Illumina HumanMethylation450 BeadChip platform. Comparatively, methylome data of solid tumours including prostate cancer, invasive breast cancer, pancreatic cancer, kidney cancer, thyroid cancer, liver cancer, rectal cancer, colon cancer, head and neck cancer, lung adenocarcinoma and lung squamous cell carcinoma collected by The Cancer Genome Atlas (TCGA) were examined. A quantitative method, bisulfite pyrosequencing, was applied to evaluate the aberrant methylation in an independent NPC patient cohort. RESULTS: In NPC, the hypermethylation pattern was more dominant than hypomethylation, where over 90% of the differentially methylated loci were hypermethylated within or close to CpG islands in tumours. The comparative methylome analysis reveals aberrant methylation at chromosome 6p frequently occurred in NPC (FDR=1.33x10-9), but was rare in other types of solid tumours. Evident enrichment of the repressive mark H3K27me3 was found at this region, indicating both DNA methylation and histone modification function together, leading to epigenetic deregulation. Bisulfite pyrosequencing results further confirmed the aberrant methylation at 6p in an additional patient cohort, and 76.9% of the early-stage NPC patients can be detected by aberrant methylation on 6p. Furthermore, aberrant methylation at this region was observed in NPC recurrent tumours and matched metastatic lymph nodes, indicating the potential use of genes in this region for prognosis. CONCLUSION: Our study highlights the importance of epigenetic deregulation in NPC. A novel genomic region on 6p with aberrant methylation was identified. This region contains several important genes that have great potential to be used as biomarkers for NPC early detection. The global genome-wide unbiased approach is useful to discover potential biomarkers for early diagnosis and prognosis in cancers. Acknowledgements: NPC AoE funding was provided by the Hong Kong Research Grants Council (AoE/M-06/08) to MLL and HKU Small Project Funding to WD.