Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma
Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma
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DOI：
10.1200/jco.2012.48.5052
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发表时间：
2013-08-10
影响因子：
45.3
通讯作者：
Tabori, Uri
中科院分区：
文献类型：
--
作者：
Zhukova, Nataliya;Ramaswamy, Vijay;Tabori, Uri
目的：详细描述TP 53突变对髓母细胞瘤预后影响的报道提供了相互矛盾的结论。我们解决这个问题，通过列入分子亚组profiles.Patients和MethodsWe确定亚组隶属关系，TP 53突变状态，并在发现队列的397髓母细胞瘤的临床结果。结果TP 53突变在无翼型（WNT; 16%）和音刺猬型（SHH; 21%）髓母细胞瘤中富集，而在第3和第4亚组中几乎不存在（P <0.001）。SHH/TP 53突变型肿瘤患者几乎全部在5 - 18岁之间，与一般SHH分布显著不同（P < .001）。患有SHH/TP 53突变型肿瘤的儿童携带56%的生殖系TP 53突变，而在患有WNT/TP 53突变型肿瘤的儿童中未观察到。TP 53突变和非TP 53突变的SHH髓母细胞瘤患者的5年总生存率（OS; +/- SE）分别为41% +/- 9%和81% +/- 5%（P <0.001）。此外，TP 53突变占SHH髓母细胞瘤5岁以上儿童死亡的72%。相比之下，有和没有TP 53突变的WNT肿瘤患者的5年OS率分别为90% +/- 9%和97% +/- 3%（P = 0.21）。多因素分析显示TP 53状态是SHH髓母细胞瘤最重要的危险因素。验证队列的生存率与发现结果相似，表明TP 53突变的生存率低仅限于SHH髓母细胞瘤患者（P = .012）而不是WNT肿瘤。结论亚组特异性分析调和了先前相互矛盾的出版物，并证实TP 53突变在SHH髓母细胞瘤中富集，其中它们预示着不良结果，并占这些患者治疗失败的很大比例。(C)2013年美国临床肿瘤学会
PurposeReports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.Patients and MethodsWe determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.ResultsTP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; +/- SE) was 41% +/- 9% and 81% +/- 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% +/- 9% and 97% +/- 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.ConclusionSubgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients. (C) 2013 by American Society of Clinical Oncology