Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations.
Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations.
复制标题
携带体细胞 TP53 突变的髓母细胞瘤儿童普遍生存率较低。
DOI：
10.1200/jco.2009.23.5952
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
C. Hawkins
中科院分区：
文献类型：
--
作者：
U. Tabori;B. Baskin;M. Shago;N. Alon;Michael D. Taylor;P. Ray;E. Bouffet;D. Malkin;C. Hawkins
目的
髓母细胞瘤是现代儿科神经肿瘤治疗成功的原型。不幸的是，20%至30%的肿瘤复发，尽管最大的切除和多模式治疗。已经研究了多种生物学预后标志物来预测复发，但关于其临床实用性仍存在争议。由于p53免疫阳性是儿童髓母细胞瘤的不良预后标志物，而TP 53突变与化疗和放疗耐药相关，我们的目的是确定TP 53突变在儿童髓母细胞瘤治疗失败中的程度和作用。
患者和方法
从1995年到2007年，我们的机构连续诊断为髓母细胞瘤的111例患者中有108例被纳入。存活者的中位随访时间为5.3年。所有样本均进行p53和erbB-2免疫染色。组织学分级和免疫染色由两名盲法评价者进行评分。对于49名患者，冷冻材料可用于TP 53测序。主要结果指标为总体生存期和无进展生存期。
结果
测序的髓母细胞瘤中有16%携带TP 53突变。作为筛选试验，p53免疫组化对TP 53突变的敏感性为100%，特异性为83%。值得注意的是，所有突变的肿瘤都在早期复发，TP 53突变型髓母细胞瘤患者的5年生存率为0%，而野生型髓母细胞瘤患者的5年生存率为74% ± 8%（P <0.0001）。此外，平均风险患者中75%的复发与TP 53突变有关。在多变量分析中，TP 53突变状态是最强的不良预后因素（风险比= 10.4，P = 0.003）。
结论
TP 53突变的髓母细胞瘤缺乏长期生存率突出了TP 53突变在髓母细胞瘤对常规治疗的耐药性中的作用，以及对替代治疗的需求，这些发现需要前瞻性验证。
PURPOSE
Medulloblastoma is the prototype of treatment success in modern pediatric neuro-oncology. Unfortunately, 20% to 30% of tumors recur despite maximal resection and multimodal therapy. Multiple biologic prognostic markers have been investigated to predict recurrences, but controversy remains regarding their clinical utility. Because p53 immunopositivity is an adverse prognostic marker in pediatric medulloblastoma and TP53 mutations are associated with chemotherapy and radiation therapy resistance, we aimed to determine the extent and role of TP53 mutations in pediatric medulloblastoma treatment failure.
PATIENTS AND METHODS
One hundred eight of 111 consecutive patients diagnosed with medulloblastoma in our institution from 1995 to 2007 were included. Median follow-up time was 5.3 years in survivors. All samples were immunostained for p53 and erbB-2. Histologic grade and immunostaining were scored by two blinded reviewers. For 49 patients, frozen material was available for TP53 sequencing. The main outcome measures were overall and progression-free survival.
RESULTS
Sixteen percent of sequenced medulloblastomas harbored a TP53 mutation. As a screening test, p53 immunohistochemistry was 100% sensitive and 83% specific for a TP53 mutation. Strikingly, all mutated tumors recurred early, and 5-year survival for average-risk patients was 0% for TP53-mutated medulloblastoma compared with 74% +/- 8% for wild-type medulloblastoma (P < .0001). Furthermore, 75% of recurrences in average-risk patients were associated with TP53 mutations. On multivariate analysis, TP53 mutation status was the strongest adverse prognostic factor (hazard ratio = 10.4, P = .003).
CONCLUSION
Lack of long-term survival in TP53-mutated medulloblastomas highlights the role of TP53 mutations in medulloblastoma resistance to conventional therapies and the need for alternative treatments, and prospective validation of these findings is needed.
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影响因子：
11.2
作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
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DOI：
10.1073/pnas.95.24.14453
发表时间：
1998-11-24
影响因子：
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作者：
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通讯作者：
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影响因子：
158.5
作者：
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