Genome-Wide Identification of a Methylation Gene Panel as a Prognostic Biomarker in Nasopharyngeal Carcinoma

Abstract

DNA methylation, the best known epigenetic marker, can be used as a prognostic biomarker in many cancers. We examined DNA methylation status and survival in nasopharyngeal carcinoma (NPC) patients. Aberrant DNA-methylated genes in 24 NPC tissues and 24 noncancer nasopharyngitis biopsy tissues (NCNBT) were identified using Illumina 450K BeadChip. Correlations between DNA methylation and clinical outcomes were evaluated using bisulfite pyrosequencing in 454 NPC patients.Genome-wide methylation analysis demonstrated that NPC tissues had distinct DNA methylation patterns compared with NCNBT. Among all significant CpG sites, 2,173 CpG sites with b change ! 0.2 (1,880 hypermethylated, 293 hypomethylated) were identified (P < 0.05). A methylation gene panel comprising six hypermethylated genes was constructed with the average Z-score method. Patients in the training cohort with high methylation had poorer disease-free survival [DFS, HR, 2.26; 95% confidence interval (CI), 1.28-4.01; P, 0.005] and overall survival (OS, HR, 2.47; 95% CI, 1.30-4.71; P, 0.006) than those with low methylation. There were similar results in the validation (DFS, HR, 2.07; 95% CI, 1.17-3.67; P, 0.013; OS, HR, 1.83; 95% CI, 1.01-3.31; P, 0.046) and independent cohorts (DFS, HR, 1.94; 95% CI, 1.08-3.47; P, 0.026; OS, HR, 2.09; 95% CI, 1.10-3.98; P, 0.022). Analysis indicated that the methylation gene panel was an independent prognostic factor. Furthermore, patients with low methylation had a favorable response to concurrent chemotherapy with an improved DFS (P ¼ 0.045) and OS (P ¼ 0.031), whereas patients with high methylation did not benefit from concurrent chemotherapy. The six-hypermethylated gene panel was associated with poor survival in patients with NPC, demonstrating its potential usefulness as a prognostic biomarker to clinicians in NPC management.

Diagnostic Capacity of RASSF1A Promoter Methylation as a Biomarker in Tissue, Brushing, and Blood Samples of Nasopharyngeal Carcinoma

“…DNA methylation, which is a common mechanism in epigenetic alterations, may be correlated with NPC (Jiang et al, 2015, Nawaz et al, 2015a). Promoter methylation of tumor suppressor genes (TSGs), such as calcium channel voltage-dependent alpha 2/delta subunit 3 ( CACNA2D3 ) and cadherin 4 ( CDH4 ), may play a crucial role in NPC development and progression (Wong et al, 2013, Du et al, 2011).…”

JMJD2A promotes the Warburg effect and nasopharyngeal carcinoma progression by transactivating LDHA expression

“…Therefore, studies identifying novel and specific biomarkers for NPC are critically important and urgently needed, with the hope of improving NPC patient’s prognosis. In addition to regular genetic regulation, epigenetic modification plays a vital role in NPC, particularly in gene methylation [3] and histone methylation [4]. However, histone demethylation, have been remained immensely uncovered in NPC mechanisms.…”

RAB37 Hypermethylation Regulates Metastasis and Resistance to Docetaxel-Based Induction Chemotherapy in Nasopharyngeal Carcinoma

“…Thus, there is a strong rationale for evaluating the interaction and enrichment of dysmethylated genes involved in identified features and signaling pathways. Although several abnormally methylated genes have been identified in NPC (14)(15)(16), their interaction and contribution to metastasis and chemoresistance remain elusive.…”