Cai Yuanxia,Wu Zhixiang,Wang Yi,et al.Expression of CDC5L in neuroblastoma and its clinical and prognostic significance[J].Journal of Clinical Pediatric Surgery,2019,18(06):472-479.[doi:10.3969/j.issn.1671-6353.2019.06.008]
CDC5L表达对神经母细胞瘤临床及预后评估的意义
- Title:
- Expression of CDC5L in neuroblastoma and its clinical and prognostic significance
- Keywords:
- Neuroblastoma; CDC5L; Pathology; Immunologic Techniques; Prognosis; Child
- 分类号:
- R729;R392.7
- 摘要:
- 目的 探讨CDC5L在神经母细胞瘤（neuroblastoma，NB）中的表达及对患儿临床和预后的影响。方法 免疫组化（immunohistochemistry，IHC）及蛋白免疫印迹（Western blot，WB）检测CDC5L在神经母细胞瘤患儿肿瘤组织中的表达，根据患儿性别、年龄、是否有骨髓浸润、肿瘤临床分期（INSS）、危险度分级、肿瘤病理诊断、Shimada病理分类及NSE、LDH是否正常进行分组，比较各组中CDC5L的表达差异，采用Kaplan-Meier和Cox回归分析CDC5L高表达组和低表达组对神经母细胞瘤生存的影响。结果 IHC显示，62例神经母细胞瘤肿瘤标本中，CDC5L高表达及低表达各31例（50%），CDC5L主要在细胞核内表达； IHC及WB均显示CDC5L在神经母细胞瘤中的表达高于节细胞神经母细胞瘤（ganglioneuroblastoma，GNB），NB和GNB均起源于原始神经嵴细胞，可于肾上腺或沿脊柱旁交感神经节分布；不同之处在于NB较GNB分化差，恶性程度更高。进一步分析CDC5L在NB患儿临床和病理特征之间的表达差异发现肿瘤骨髓浸润组较无肿瘤浸润组CDC5L高表达的比例更高，差异有统计学意义（χ2=5.833，P=0.016）；CDC5L在肿瘤临床分期Ⅲ~Ⅳ中的高表达比例高于Ⅰ~Ⅱ和Ⅳ-S期，差异有统计学意义（χ2=11.328，P=0.001）；CDC5L高表达的比例在MYCN扩增组高于MYCN非扩增组（P=0.038）；危险度分级中，高危患儿中CDC5L表达增高的比例较中危和低危患儿高（χ2=9.378，P=0.002）；Shimada病理分类中，不良组织学类型较良好组织学类型CDC5L表达增高的比例更高（χ2=7.839，P=0.005）；NSE升高组较NSE正常组CDC5L表达增高的比例更高（P=0.035）；LDH ≥ 587 U/L较LDH < 587 U/L有更高比例的CDC5L表达增高，差异有统计学意义（χ2=5.547，P=0.019）。Kaplan-Meier生存分析提示CDC5L高表达组3年存活率（48.8% vs. 88.0%）低于CDC5L低表达组，差异有统计学意义（P=0.002）。单因素Cox回归分析发现CDC5L高表达（HR=4.734，95%CI：1.590~14.091）、临床分期为Ⅲ和Ⅳ期（HR=7.444，95%CI：2.187~25.339）、高危状态（HR=2.749，95%CI：1.454~5.194）、Shimada 病理UFH型（HR=4.098，95%CI：1.493~11.250）均是NB患儿预后的危险因素。但是进一步多因素Cox回归分析发现上述因素均没有统计学差异（P>0.05） 结论 CDC5L的表达和已知的患儿预后危险因素、不良病理类型及肿瘤标志物升高有较好的一致性，且生存分析也提示CDC5L高表达组较低表达组差，因此CDC5L可作为潜在的提示神经母细胞瘤患儿具有不良预后、不良病理类型和肿瘤标志物升高的分子标志物。
- Abstract:
- Objective To explore the expression of CDC5L and its influence on clinicopathological characteristics in children of neuroblastoma (NB). Methods The expression of CDC5L was detected by immunohistochemistry (IHC) and Western blot (WB) in 62 NB specimens. They were divided into several groups according to gender,age,metastasis of bone marrow,tumor clinical stage (INSS),risk rating,pathological diagnosis,Shimada pathological classification and the results of lactate dehydrogenase (LDH) and neuron specific enolase (NSE). Then the difference of CDC5L expression between groups was analyzed by chi-square test. We also analyzed the overall survival rate between low and high CDC5L expression groups in 50 NB patients with complete follow-up data using Kaplan-Meier and COX regression.Results Immunohistochemical staining showed that CDC5L was predominantly located at nucleus of NB cells. Both high and low expressions of CDC5L were detected in 31/62 NB patients (50%). Both IHC and WB showed that CDC5L was more strongly expressed in NB than ganglioneuroblastoma (GNB). Both NB and GNB were derived from neural crest cells,might arise in adrenal medulla or anywhere along paraspinal sympathetic ganglia while NB was less differentiated and more malignant; We further analyzed the relationship between CDC5L expression and other clinicopathological characteristics. It was found that CDC5L expression level was higher in bone marrow infiltration group than that in non-infiltration group (χ2=5.833,P=0.016). The expression of CDC5L was higher in stage Ⅲ-Ⅳ cases than that in stage Ⅰ-Ⅱ/Ⅳ-S cases (χ2=11.328,P=0.001). Overexpression of CDC5L was usually accompanied by a frequent amplification of MYCN and amplification status of MYCN was different between high and low expression groups of CDC5L (P=0.038); CDC5L was more abundant in high-risk group than in low/intermediate-risk group (χ2=9.378,P=0.002). According to the pathological classification of Shimada,unfavorable histologic category (UFH) cases had a higher expression of CDC5L than favorable histologic category cases (χ2=7.839,P=0.005). The expression of CDC5L was higher in NSE-elevated group than that in NSE-normal group (P=0.035). Cases with LDH ≥ 587 U/L had a higher expression of CDC5L (χ2=5.547,P=0.019). Both Kaplan-Meier (P=0.002) and COX regression (HR=4.734,95%CI:1.590-14.091) showed that overexpression of CDC5L had a poor clinical prognosis. In addition,higher clinical stage (HR=7.444,95%CI:2.187-25.339),high-risk state (HR=2.749,95%CI:1.454-5.194) and pathological UFH type (HR=4.098,95%CI:1.493-11.250) were associated with worse clinical outcomes. However,when the above factors were further analyzed by COX multivariate regression,no statistical difference was observed. Conclusion A high expression of CDC5L is highly consistent with prognostic risk factors,adverse pathological types and elevated tumor markers. Kaplan-Meier curves also shows that low CDC5L group has longer survival time than high CDC5L group. Therefore CDC5L may be used as a potential molecular marker of poor prognosis,poor pathological type and elevation of tumor makers in NB children.
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备注/Memo
收稿日期:2018-04-03。
基金项目:国家自然科学基金（编号：81572918）；国家自然科学基金（编号：81874234）；国家自然科学基金（编号：81672488）；上海市启明星计划（编号：16QA1402900）；苏州市"临床医学专家团队"引进项目（编号：SZYJTD201706）
通讯作者:吴晔明,Email:wuyeming@xinhuamed.com.cn