Tumor Genetics and Epigenetics, IRCCS AOU San Martino-IST, Genova, Italy.
PLoS One. 2013 May 22;8(5):e63253. doi: 10.1371/journal.pone.0063253. Print 2013.
Approximately 20% of stage 4 high-risk neuroblastoma patients are alive and disease-free 5 years after disease onset while the remaining experience rapid and fatal progression. Numerous findings underline the prognostic role of methylation of defined target genes in neuroblastoma without taking into account the clinical and biological heterogeneity of this disease. In this report we have investigated the methylation of the PCDHB cluster, the most informative member of the "Methylator Phenotype" in neuroblastoma, hypothesizing that if this epigenetic mark can predict overall and progression free survival in high-risk stage 4 neuroblastoma, it could be utilized to improve the risk stratification of the patients, alone or in conjunction with the previously identified methylation of the SFN gene (14.3.3sigma) that can accurately predict outcome in these patients. We have utilized univariate and multivariate models to compare the prognostic power of PCDHB methylation in terms of overall and progression free survival, quantitatively determined by pyrosequencing, with that of other markers utilized for the patients' stratification utilizing methylation thresholds calculated on neuroblastoma at stage 1-4 and only on stage 4, high-risk patients. Our results indicate that PCDHB accurately distinguishes between high- and intermediate/low risk stage 4 neuroblastoma in agreement with the established risk stratification criteria. However PCDHB cannot predict outcome in the subgroup of stage 4 patients at high-risk whereas methylation levels of SFN are suggestive of a "methylation gradient" associated with tumor aggressiveness as suggested by the finding of a higher threshold that defines a subset of patients with an extremely severe disease (OS <24 months). Because of the heterogeneity of neuroblastoma we believe that clinically relevant methylation markers should be selected and tested on homogeneous groups of patients rather than on patients at all stages.
约 20%的 4 期高危神经母细胞瘤患者在发病后 5 年仍存活且无疾病，而其余患者则迅速且致命地进展。许多研究结果强调了在不考虑该病临床和生物学异质性的情况下，特定靶基因甲基化在神经母细胞瘤中的预后作用。在本报告中，我们研究了 PCDHB 簇的甲基化，PCDHB 簇是神经母细胞瘤中“甲基化表型”最具信息性的成员，假设如果这种表观遗传标记可以预测高危 4 期神经母细胞瘤的总生存率和无进展生存率，那么它可以单独或与先前确定的 SFN 基因（14.3.3sigma）甲基化一起用于改善患者的风险分层，SFN 基因甲基化可以准确预测这些患者的结局。我们利用单变量和多变量模型来比较 pyrosequencing 定量测定的 PCDHB 甲基化在总生存率和无进展生存率方面的预后能力，并与其他用于分层的标志物进行比较，这些标志物是利用神经母细胞瘤 1-4 期和仅 4 期高危患者计算的甲基化阈值来确定的。我们的研究结果表明，PCDHB 可以准确地区分高风险和中低风险的 4 期神经母细胞瘤，与既定的风险分层标准一致。然而，PCDHB 不能预测高危 4 期患者亚组的结局，而 SFN 的甲基化水平提示存在与肿瘤侵袭性相关的“甲基化梯度”，这是通过发现更高的阈值来定义一组具有极严重疾病（OS<24 个月）的患者亚群得出的。由于神经母细胞瘤的异质性，我们认为应该在同质的患者群体中选择和测试临床相关的甲基化标志物，而不是在所有阶段的患者中进行。
