Department of Molecular Oncology, John Wayne Cancer Institute (JWCI) at St. John's Health Center, 2200 Santa Monica Boulevard, Santa Monica, CA, 90404, USA.
Breast Cancer Res Treat. 2012 Feb;131(3):859-69. doi: 10.1007/s10549-011-1485-3. Epub 2011 Apr 11.
Breast cancer patients with similar clinical stage may experience different disease outcomes. Aberrant DNA methylation of primary breast tumors can have impact on the clinical outcome. This study aimed to assess clinical utility of tumor-specific methylated sequences (MINT17, 31) and tumor-related gene (RARβ2) methylation classification in primary breast tumors. Absolute quantitative assessment of methylated alleles (AQAMA) was used to determine the methylation index (MI) of MINT17, MINT31, and RARß2 in 242 primary tumors of early stage breast cancer patients. Patients were classified into three methylation groups: meth-N, with normal methylation levels of all biomarkers; meth-L, with one biomarker hypermethylation; and meth-H, with hypermethylation of >1 biomarker. Disease outcome of methylation groups was compared during follow-up. MI of all biomarkers was successfully obtained in 237 tumors of which 79 (33%) were classified as meth-N, 86 (36%) as meth-L, and 72 (30%) as meth-H. Meth-H status was a risk factor for distant recurrence (DR) (log-rank P = 0.007) and shorter disease-free survival (DFS) (log-rank P = 0.039). Methylation classification had strongest prognostic value for patients with ER-negative tumors. In multivariate analysis (n = 222), ER-negative meth-H patients had a 4.1-fold increased risk of DR (95% CI 1.80-9.59; meth-N HR 1.0, P = 0.001), a 4.2-fold increased risk of overall recurrence (OR) (95% CI 1.88-9.47; meth-N HR 1.0, P = 0.001), and a 3.1-fold shorter DFS (95% CI 1.57-5.98; meth-N HR 1.0, P = 0.003). Methylation classification of primary breast cancer is an independent prognostic factor for disease outcome in patients with ER-negative tumors. The study's findings will have to be confirmed in an independent dataset.
患有相似临床分期的乳腺癌患者可能会经历不同的疾病结局。原发性乳腺癌中异常的 DNA 甲基化可能会对临床结局产生影响。本研究旨在评估肿瘤特异性甲基化序列（MINT17、31）和肿瘤相关基因（RARβ2）甲基化分类在原发性乳腺癌中的临床应用价值。使用绝对定量评估甲基化等位基因（AQAMA）来确定 242 例早期乳腺癌患者的原发性肿瘤中 MINT17、MINT31 和 RARß2 的甲基化指数（MI）。将患者分为三个甲基化组：meth-N，所有生物标志物的甲基化水平正常；meth-L，一个生物标志物发生高甲基化；meth-H，超过 1 个生物标志物发生高甲基化。在随访期间比较各组的疾病结局。在 237 例肿瘤中成功获得了所有生物标志物的 MI，其中 79 例（33%）被分类为 meth-N，86 例（36%）为 meth-L，72 例（30%）为 meth-H。meth-H 状态是远处复发（DR）（对数秩 P = 0.007）和无病生存（DFS）（对数秩 P = 0.039）较短的危险因素。对于 ER 阴性肿瘤患者，甲基化分类具有最强的预后价值。在多变量分析（n = 222）中，ER 阴性 meth-H 患者 DR 的风险增加了 4.1 倍（95%CI 1.80-9.59；meth-N HR 1.0，P = 0.001），总复发（OR）的风险增加了 4.2 倍（95%CI 1.88-9.47；meth-N HR 1.0，P = 0.001），DFS 缩短了 3.1 倍（95%CI 1.57-5.98；meth-N HR 1.0，P = 0.003）。原发性乳腺癌的甲基化分类是 ER 阴性肿瘤患者疾病结局的独立预后因素。研究结果需要在独立数据集进行验证。
