Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates.
Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates.
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DOI：
10.1111/cas.12928
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发表时间：
2016-06
期刊：
影响因子：
5.7
通讯作者：
Taketomi A
中科院分区：
文献类型：
--
作者：
Honda S;Minato M;Suzuki H;Fujiyoshi M;Miyagi H;Haruta M;Kaneko Y;Hatanaka KC;Hiyama E;Kamijo T;Okada T;Taketomi A
肝母细胞瘤（HB）是非常罕见的，但最常见的肝脏恶性肿瘤发生在儿童。尽管在治疗方面有所改进，但标准术前化疗难治的晚期HB患者的结局仍不令人满意。为了提高这一群体的生存率，需要鉴定新的预后标志物和治疗靶点。我们以前曾报道过，改变DNA甲基化模式在HB中具有生物学和临床重要性。在本研究中，使用全基因组甲基化分析和亚硫酸氢盐焦磷酸测序，从HB肿瘤标本中，我们检测到9个甲基化基因。然后，我们集中研究了其中的四个基因，GPR180，MST1R，OCIAD 2和PARP6，因为它们可能编码肿瘤抑制因子，并且它们的甲基化增加与预后不良相关。四个基因的甲基化状态也与诊断时的年龄相关，并且在四个基因中的三个中观察到与转移性肿瘤的存在的显著关联。多因素分析显示，转移性肿瘤的存在和GPR180甲基化的增加是影响无事件生存期的独立预后因素。这些发现表明，四种新的肿瘤抑制候选物是预测HB患者不良结局的潜在有用的分子标记物，这可能作为临床试验进行时改进治疗策略的基础。
Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome‐wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180,MST1R,OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event‐free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.