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 β 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 = 0.045) and OS (P = 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.
Highlights
Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia, whereas it is rare in most of the other parts around the world; the age-standardized incidence per 100,000 males ranges 20 to 50 in Southern China as compared with 0.5 in Western countries [1]
In order to identify biologically meaningful methylation changes, 780 hypermethylated CpG sites were selected for further analysis from 2,173 CpG sites based on the following exclusion criteria: (i) hypomethylated CpG sites; (ii) mean noncancer nasopharyngitis biopsy tissues (NCNBT) methylation level >25%; (iii) CpG sites not located in proximal promoter regions [including transcription start site (TSS) 1,500 and TSS200, 50UTR, and first exon]; (iv) all imprinted and X chromosome genes (Fig. 2)
We examined the mRNA expression of these 28 genes in the 24 NPC tissues and NCNBT: only eight genes had >2-fold downregulation in the NPC tissues (Fig. 3A)
Summary
Nasopharyngeal carcinoma (NPC) is a common malignancy in Southern China and Southeast Asia, whereas it is rare in most of the other parts around the world; the age-standardized incidence per 100,000 males ranges 20 to 50 in Southern China as compared with 0.5 in Western countries [1].
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