Yang Qiwei, Kiernan Colleen M, Tian Yufeng, Salwen Helen R, Chlenski Alexandre, Brumback Babette A, London Wendy B, Cohn Susan L
The Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA.
Clin Cancer Res. 2007 Jun 1;13(11):3191-7. doi: 10.1158/1078-0432.CCR-06-2846.
Epigenetic aberrations have been shown to play an important role in the pathogenesis of most cancers. To investigate the clinical significance of epigenetic changes in neuroblastoma, we evaluated the relationship between clinicopathologic variables and the pattern of gene methylation in neuroblastoma cell lines and tumors.
Methylation-specific PCR was used to evaluate the gene methylation status of 19 genes in 14 neuroblastoma cell lines and 8 genes in 70 primary neuroblastoma tumors. Associations between gene methylation, established prognostic factors, and outcome were evaluated. Log-rank tests were used to identify the number of methylated genes that was most predictive of overall survival.
Epigenetic changes were detected in the neuroblastoma cell lines and primary tumors, although the pattern of methylation varied. Eight of the 19 genes analyzed were methylated in >70% of the cell lines. Epigenetic changes of four genes were detected in only small numbers of cell lines. None of the cell lines had methylation of the other seven genes analyzed. In primary neuroblastoma tumors, high-risk disease and poor outcome were associated with methylation of DCR2, CASP8, and HIN-1 individually. Although methylation of the other five individual genes was not predictive of poor outcome, a trend toward decreased survival was seen in patients with a methylation phenotype, defined as > or =4 methylated genes (P = 0.055).
Our study indicates that clinically aggressive neuroblastoma tumors have aberrant methylation of multiple genes and provides a rationale for exploring treatment strategies that include demethylating agents.
表观遗传异常已被证明在大多数癌症的发病机制中起重要作用。为了研究神经母细胞瘤表观遗传变化的临床意义，我们评估了神经母细胞瘤细胞系和肿瘤中临床病理变量与基因甲基化模式之间的关系。
采用甲基化特异性PCR评估14种神经母细胞瘤细胞系中19个基因的基因甲基化状态以及70例原发性神经母细胞瘤肿瘤中8个基因的甲基化状态。评估基因甲基化、既定预后因素与预后之间的关联。使用对数秩检验来确定最能预测总生存期的甲基化基因数量。
在神经母细胞瘤细胞系和原发性肿瘤中检测到表观遗传变化，尽管甲基化模式各不相同。所分析的19个基因中有8个在>70%的细胞系中发生甲基化。仅在少数细胞系中检测到4个基因的表观遗传变化。所分析的其他7个基因在任何细胞系中均未发生甲基化。在原发性神经母细胞瘤肿瘤中，高危疾病和不良预后分别与DCR2、CASP8和HIN-1的甲基化相关。虽然其他5个单个基因的甲基化不能预测不良预后，但在具有甲基化表型（定义为≥4个甲基化基因）的患者中观察到生存下降的趋势（P = 0.055）。
我们的研究表明，临床上侵袭性神经母细胞瘤肿瘤存在多个基因的异常甲基化，并为探索包括去甲基化剂在内的治疗策略提供了理论依据。
