Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct.
Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct.
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DOI：
10.1007/s00401-011-0846-7
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发表时间：
2011-08
影响因子：
12.7
通讯作者：
Taylor MD
中科院分区：
文献类型：
--
作者：
Northcott PA;Hielscher T;Dubuc A;Mack S;Shih D;Remke M;Al-Halabi H;Albrecht S;Jabado N;Eberhart CG;Grajkowska W;Weiss WA;Clifford SC;Bouffet E;Rutka JT;Korshunov A;Pfister S;Taylor MD
最近的综合基因组方法已经定义了在遗传和临床上不同的髓母细胞瘤分子亚组。音刺猬 (Shh) 髓母细胞瘤占所有病例的三分之一，占婴儿和成人髓母细胞瘤的大多数。为了辨别 Shh 髓母细胞瘤之间的分子异质性，我们分析了四个独立的 Shh 髓母细胞瘤表达数据集 (n = 66) 的转录谱。无监督聚类分析表明婴儿和成人 Shh 髓母细胞瘤之间存在明显区别，并且在各个数据集中可靠地复制了这一点。婴儿和成人 Shh 髓母细胞瘤转录组的比较揭示了多个基因家族的失调，包括与细胞发育、突触发生和细胞外基质维持有关的基因。此外，转移性播散是成人预后不良的标志，但对于儿童 Shh 髓母细胞瘤则不然。患有促纤维增生性 Shh 髓母细胞瘤的儿童比患有 Shh 髓母细胞瘤和经典组织学的儿童预后更好。结缔组织增生不能作为成人 Shh 髓母细胞瘤的预后。对大型、非重叠的 Shh 髓母细胞瘤队列 (n = 151) 进行的细胞遗传学分析显示，与成人相比，儿科 Shh 病例中染色体 10q 缺失 (P < 0.001) 和 MYCN 扩增 (P < 0.05) 的比例显着过高。与表现出相同畸变的儿科病例相比，携带染色体 10q 缺失、2 增益、17p 缺失、17q 增益和/或 GLI2 扩增的成人 Shh 髓母细胞瘤的预后要差得多。总的来说，我们的数据表明，儿童和成人 Shh 髓母细胞瘤在临床、转录、遗传和预后方面都有所不同。
Recent integrative genomic approaches have defined molecular subgroups of medulloblastoma that are genetically and clinically distinct. Sonic hedgehog (Shh) medulloblastomas account for one-third of all cases and comprise the majority of infant and adult medulloblastomas. To discern molecular heterogeneity among Shh-medulloblastomas, we analyzed transcriptional profiles from four independent Shh-medulloblastoma expression datasets (n = 66). Unsupervised clustering analyses demonstrated a clear distinction between infant and adult Shh-medulloblastomas, which was reliably replicated across datasets. Comparison of transcriptomes from infant and adult Shh-medulloblastomas revealed deregulation of multiple gene families, including genes implicated in cellular development, synaptogenesis, and extracellular matrix maintenance. Furthermore, metastatic dissemination is a marker of poor prognosis in adult, but not in pediatric Shh-medulloblastomas. Children with desmoplastic Shh-medulloblastomas have a better prognosis than those with Shh-medulloblastomas and classic histology. Desmoplasia is not prognostic for adult Shh-medulloblastoma. Cytogenetic analysis of a large, non-overlapping cohort of Shh-medulloblastomas (n = 151) revealed significant over-representation of chromosome 10q deletion (P < 0.001) and MYCN amplification (P < 0.05) in pediatric Shh cases compared with adults. Adult Shh-medulloblastomas harboring chromosome 10q deletion, 2 gain, 17p deletion, 17q gain, and/or GLI2 amplification have a much worse prognosis as compared to pediatric cases exhibiting the same aberrations. Collectively, our data demonstrate that pediatric and adult Shh-medulloblastomas are clinically, transcriptionally, genetically, and prognostically distinct.