Promoter Methylation As Biomarkers For Diagnosis Of Melanoma: A Systematic Review And Meta-Analysis

Melanoma is one of the most common skin cancer that is characterized by rapid growth, early metastasis, high malignant, and mortality. Accumulating evidence demonstrated that promoter methylation of tumor-suppressor genes is implicated in the pathogenesis of melanoma. In the current study, we performed a meta-analysis to identify promising methylation biomarkers in the diagnosis of melanoma. We carried out a systematic literature search using Pubmed, Embase, and ISI web knowledge database and found that gene promoter methylation of 50 genes was reported to be associated with the risk of melanoma. Meta-analysis revealed that hypermethylation of claudin 11 (CLDN11; odds ratio [OR], 16.82; 95% confidence interval [CI], 1.97-143.29; p = 0.010), O-6-methylguanine-DNA methyltransferase (MGMT; OR, 5.59; 95% CI, 2.51-12.47; p < 0.0001), cyclin-dependent kinase inhibitor 2A (p16; OR, 6.57; 95% CI, 2.19-19.75; p = 0.0008), retinoic acid receptor beta (RAR-beta 2; OR, 24.31; 95% CI, 4.58-129.01; p = 0.0002), and Ras association domain family member (RASSF1A; OR, 9.35; 95% CI, 4.73-18.45; p < 0.00001) was significantly higher in melanoma patients compared with controls. CLDN11 (OR, 14.52; 95% CI, 1.84-114.55; p = 0.01), MGMT (OR, 8.08; 95% CI, 1.84-35.46; p = 0.006), p16 (OR, 9.44; 95% CI, 2.68-33.29; p = 0.0005), and RASSF1A (OR, 7.72; 95% CI, 1.05-56.50; p = 0.04) hypermethylation was significantly increased in primary melanoma compared with controls. Methylation frequency of CLDN11 (OR, 25.56; 95% CI, 2.32-281.66; p = 0.008), MGMT (OR, 4.64; 95% CI, 1.98-10.90; p = 0.0004), p16 (OR, 4.31; 95% CI, 1.33-13.96; p = 0.01), and RASSF1A (OR, 10.10; 95% CI, 2.87-35.54; p = 0.0003) was significantly higher in metastasis melanoma compared with controls. These findings indicated that CLDN11, MGMT, p16, RAR-beta 2, and RASSF1A hypermethylation is a risk factor and a potential biomarker for melanoma. CLDN11, MGMT, p16, and RASSF1A promoter methylation may take part in the development of melanoma and become useful biomarkers in the early diagnosis of the disease.