The role of estrogen receptor α (ER-α) in melanoma is unknown. ER-α expression may be regulated in melanoma via hypermethylation of promoter CpG islands. We assessed ER-α hypermethylation in primary and metastatic melanomas and sera as a potential tumor progression marker. ER-α methylation status in tumor (n = 107) and sera (n = 109) from American Joint Committee on Cancer (AJCC) stage I to IV melanoma patients was examined by methylation-specific PCR. The clinical significance of serum methylated ER-α was assessed among AJCC stage IV melanoma patients receiving biochemotherapy with tamoxifen. Rates of ER-α methylation in AJCC stage I, II, and III primary melanomas were 36% (4 of 11), 26% (5 of 19), and 35% (8 of 23), respectively. Methylated ER-α was detected in 42% (8 of 19) of stage III and 86% (30 of 35) of stage IV metastatic melanomas. ER-α was methylated more frequently in metastatic than primary melanomas (P = 0.0003). Of 109 melanoma patients' sera in AJCC stage I, II, III, and IV, methylated ER-α was detected in 10% (2 of 20), 15% (3 of 20), 26% (5 of 19), and 32% (16 of 50), respectively. Serum methylated ER-α was detected more frequently in advanced than localized melanomas (P = 0.03) and was the only factor predicting progression-free [risk ratio (RR), 2.64; 95% confidence interval (95% CI), 1.36-5.13; P = 0.004] and overall survival (RR, 2.31; 95% CI, 1.41-5.58; P = 0.003) in biochemotherapy patients. Hypermethylated ER-α is a significant factor in melanoma progression. Serum methylated ER-α is an unfavorable prognostic factor.
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