Adult Medulloblastoma Comprises Three Major Molecular Variants
Adult Medulloblastoma Comprises Three Major Molecular Variants
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DOI：
10.1200/jco.2011.34.9373
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发表时间：
2011-07-01
影响因子：
45.3
通讯作者：
Korshunov, Andrey
中科院分区：
文献类型：
--
作者：
Remke, Marc;Hielscher, Thomas;Korshunov, Andrey
目的髓母细胞瘤是一种罕见的成人原发性脑肿瘤，而它是儿童最常见的恶性脑肿瘤。综合基因组学方法揭示了儿童中至少四种不同的疾病变体。本研究的目的是探讨分子亚型及其预后意义在一个大的队列成人髓母细胞瘤的生物学在这个年龄组仍然知之甚少。患者和MethodsWe结合转录组和DNA拷贝数分析28成人髓母细胞瘤。应用统计和生物信息学工具来发现不同的分子变体。每个生物亚型的临床和分子特征进行了验证，来自一个独立的患者队列的成人髓母细胞瘤（n = 103）。ResultsGene表达谱的组织微阵列上使用免疫组化揭示了三个不同的分子变异与稳定的亚型分离使用300个最不同的成绩单。不同的人口统计学，遗传学，转录组，和预后的成人髓母细胞瘤的每一个亚型。免疫组化显示，在超过一半的成人髓母细胞瘤中，音刺猬（SHH）通路异常激活，构成了一个有前途的分子治疗靶点。相比之下，C亚型肿瘤，其中包括一个强大的亚型在儿童髓母细胞瘤只例外地看到在成人队列。值得注意的是，成人亚型D和Wnt/wingless肿瘤与儿童队列预后较差，而SHH肿瘤的生存率是相似的两个年龄组conclusionThe转录组的成人髓母细胞瘤有很大不同，从儿科同行，无论是在肿瘤生物学和预后的影响。因此，年龄特异性分类是必需的，并且必须适用于成人髓母细胞瘤的临床试验。
PurposeMedulloblastoma is a rare primary brain tumor in adults, whereas it constitutes the most common malignant brain tumor in children. Integrated genomics approaches revealed at least four distinct disease variants in children. The aim of this study was to investigate molecular subtypes and their prognostic implication in a large cohort of adult medulloblastomas as the biology in this age group remains poorly understood.Patients and MethodsWe combined transcriptome and DNA copy number analyses for 28 adult medulloblastomas. Statistical and bioinformatic tools were applied to discover distinct molecular variants. Clinical and molecular characteristics of each biologic subtype were validated using immunohistochemistry on a tissue microarray derived from an independent patient cohort of adult medulloblastomas (n = 103).ResultsGene expression profiles revealed three distinct molecular variants with stable subtype separation using the 300 most varying transcripts. Distinct demographics, genetics, transcriptome, and prognosis were noted for each subtype of adult medulloblastoma. Immunohistochemistry revealed aberrant activation of the sonic hedgehog (SHH) pathway in over half of adult medulloblastomas constituting a promising molecular therapeutic target. In contrast, subtype C tumors, which comprise a robust subtype in childhood medulloblastoma are only exceptionally seen in adult cohorts. Notably, adult subtype D and Wnt/wingless tumors were associated with worse prognosis than pediatric cohorts, whereas survival for SHH tumors was similar for both age groups.ConclusionThe transcriptome of adult medulloblastomas differs considerably from pediatric counterparts, both in terms of tumor biology and prognostic impact. Therefore, age-specific classification is required and must be adapted for use in clinical trials of adult medulloblastoma.