Robbins Charles J, Bou-Dargham Mayassa J, Sanchez Kevin, Rosen Matthew C, Sang Qing-Xiang Amy
Department of Chemistry & Biochemistry, Institute of Molecular Biophysics, Florida State University.
J Cancer. 2018 Nov 17;9(24):4596-4610. doi: 10.7150/jca.27993. eCollection 2018.
Medulloblastoma is the most common malignant pediatric brain tumor. Prior studies have concentrated their efforts studying the four molecular subgroups: SHH, Wnt, group 3, and group 4. SHH and Wnt are driven by their canonical pathways. Groups 3 and 4 are highly metastatic and associated with aberrations in epigenetic regulators. Recent developments in the field have revealed that these subgroups are not as homogenous as previously believed. The objective of this study is to investigate the involvement of somatic driver gene mutations in these medulloblastoma subgroups. We obtained medulloblastoma data from the Catalogue of Somatic Mutations in Cancer (COSMIC), which contains distinct samples that were not previously studied in a large cohort. We identified somatic driver gene mutations and the signaling pathways affected by these driver genes for medulloblastoma subgroups using bioinformatics tools. We have revealed novel infrequent drivers in these subgroups that contribute to our understanding of tumor heterogeneity in medulloblastoma. Normally SHH signaling is activated in the SHH subgroup, however, we determined gain-of-function mutations in ubiquitin ligase ( that inhibit Gli-mediated transcription. This suggests a potential hindrance in SHH signaling for some patients. For group 3, gain-of-function in the inhibitor of proinflammatory cytokines () suggests an immunosuppressive phenotype and thus a more hostile tumor microenvironment. Surprisingly, group 4 tumors possess mutations that may prompt the activation of Wnt signaling through gain-of-function mutations in and . These infrequent mutations detected in this study could be due to subclonal or spatially restricted alterations. The investigation of aberrant driver gene mutations can lead to the identification of new drug targets and a greater understanding of human medulloblastoma heterogeneity.
髓母细胞瘤是最常见的儿童恶性脑肿瘤。先前的研究主要集中在四个分子亚组：SHH、Wnt、3组和4组。SHH和Wnt由其经典信号通路驱动。3组和4组具有高度转移性，且与表观遗传调节因子的异常有关。该领域的最新进展表明，这些亚组并不像之前认为的那样同质化。本研究的目的是调查体细胞驱动基因突变在这些髓母细胞瘤亚组中的作用。我们从癌症体细胞突变目录（COSMIC）中获取了髓母细胞瘤数据，该目录包含了此前未在大型队列中研究过的不同样本。我们使用生物信息学工具识别了髓母细胞瘤亚组的体细胞驱动基因突变以及受这些驱动基因影响的信号通路。我们在这些亚组中发现了新的罕见驱动基因，这有助于我们理解髓母细胞瘤中的肿瘤异质性。通常情况下，SHH信号通路在SHH亚组中被激活，然而，我们确定了泛素连接酶中的功能获得性突变（其抑制Gli介导的转录）。这表明一些患者的SHH信号通路可能存在潜在障碍。对于3组，促炎细胞因子抑制剂（）中的功能获得性突变表明其具有免疫抑制表型，因此肿瘤微环境更具敌意。令人惊讶的是，4组肿瘤具有可能通过和中的功能获得性突变促使Wnt信号通路激活的突变。本研究中检测到的这些罕见突变可能是由于亚克隆或空间受限的改变。对异常驱动基因突变的研究可以导致新药物靶点的识别，并加深对人类髓母细胞瘤异质性的理解。
