The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients
The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients
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DOI：
10.1002/ijc.23613
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发表时间：
2008-09-01
影响因子：
6.4
通讯作者：
Kaneko, Yasuhiko
中科院分区：
文献类型：
--
作者：
Honda, Shohei;Haruta, Masayuki;Kaneko, Yasuhiko
尽管治疗取得了进展，但对标准术前化疗无效的晚期肝母细胞瘤患者的结果仍然不令人满意。为了降低死亡率，需要新的预后标志物来制定更好的治疗计划。我们通过传统的甲基化特异性 PCR (MSP) 检查了 20 个肝母细胞瘤肿瘤中 13 个候选肿瘤抑制基因的甲基化状态，发现 13 个基因中有 3 个存在高甲基化。我们分析了 97 个肿瘤中这 3 个基因（RASSFIA、SOCS1 和 CASP8）的甲基化状态，发现高甲基化率分别为 30.9%、33.0% 和 15.5%。单变量分析显示，只有 RASSFIA 的甲基化状态而不是其他 2 个基因可以预测结果，多变量分析显示 RASSFIA 甲基化对总生存期的贡献较弱。使用定量 MSP，我们发现 97 个肿瘤中有 44.3% 存在 RASSFIA 甲基化。 97 个肿瘤中 67.0% 检测到 CTNNB1 突变。虽然单变量分析表明 RASSFIA 甲基化、CTNNB1 突变和其他临床病理变量是预后因素，但多变量分析确定 RASSFIA 甲基化（p = 0.043；相对风险 9.39）和疾病分期（p = 0.002；相对风险 7.67）而非 CTNNB1 突变为独立预后因素。在对 313 或 4 期 33 名患者进行的生存分析中，未甲基化肿瘤患者的总体生存率高于甲基化肿瘤患者（p = 0.035）。 RASSFIA 甲基化可能是预测治疗结果的有前途的分子遗传学标记，并且可用于在进行临床试验时对患者进行分层。 (C) 2008 Wiley-Liss, Inc.
Despite the progress of therapy, outcomes of advanced hepatoblastoma patients who are refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the mortality rate, novel prognostic markers are needed for better therapy planning. We examined the methylation status of 13 candidate tumor suppressor genes in 20 hepatoblastoma tumors by conventional methylation-specific PCR (MSP) and found hypermethylation in 3 of the 13 genes. We analyzed the methylation status of these 3 genes (RASSFIA, SOCS1 and CASP8) in 97 tumors and found hypermethylation in 30.9, 33.0 and 15.5%, respectively. Univariate analysis showed that only the methylation status of RASSFIA but not the other 2 genes predicted the outcome, and multivariate analysis showed a weak contribution of RASSFIA methylation to overall survival. Using quantitative MSP, we found RASSFIA methylation in 44.3% of the 97 tumors. CTNNB1 mutation was detected in 67.0% of the 97 tumors. While univariate analysis demonstrated RASSFIA methylation, CTNNB1 mutation and other clinicopathological variables as prognostic factors, multivariate analysis identified RASSFIA methylation (p = 0.043; relative risk 9.39) and the disease stage (p = 0.002; relative risk 7.67) but not CTNNB1 mutation as independent prognostic factors. In survival analysis of 33 patients in stage 313 or 4, patients with unmethylated tumor had better overall survival than those with methylated tumor (p = 0.035). RASSFIA methylation may be a promising moleculargenetic marker to predict the treatment outcome and may be used to stratify patients when clinical trials are carried out. (C) 2008 Wiley-Liss, Inc.