Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
Integrated Molecular Characterization of the Lethal Pediatric Cancer Pancreatoblastoma
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DOI：
10.1158/0008-5472.can-17-2581
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发表时间：
2018-02-15
期刊：
影响因子：
11.2
通讯作者：
Takita, Junko
中科院分区：
文献类型：
--
作者：
Isobe, Tomoya;Seki, Masafumi;Takita, Junko
胰腺母细胞瘤是一种罕见的儿童胰腺恶性肿瘤，其分子发病机制尚不清楚。在这项研究中，我们报告了一个完整的外显子组和RNA测序以及全基因组拷贝数和甲基化分析的10例胰腺母细胞瘤的多组学研究的结果。胰腺母细胞瘤基因组的特征在于Wnt信号通路的高频率异常激活，通过CTNNB 1的体细胞突变（90%）和APC的拷贝中性杂合性丢失（CN-LOH）（10%）。此外，普遍检测到CN-LOH（80%）、父本等位基因获得（10%）和甲基化获得（10%）导致的IGF 2印迹失调。在转录组水平，胰腺母细胞瘤表现出早期胰腺祖细胞样细胞的表达特征，沿着R-spondin/LGR 5/RNF 43模块的上调。我们的研究结果提供了一个全面的描述胰腺母细胞瘤的分子基础，并突出合理的治疗靶点，其treatment.Significance：一种罕见的无法治疗的儿科肿瘤的分子遗传学分析揭示了Wnt/IGF 2畸变和早期胰腺祖细胞样细胞的功能，这表明细胞起源和合理的治疗靶向策略。(C)2017年AACR。
Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%). In addition, imprinting dysregulation of IGF2 as a consequence of CN-LOH (80%), gain of paternal allele (10%), and gain of methylation (10%) was universally detected. At the transcriptome level, pancreatoblastoma exhibited an expression profile characteristic of early pancreas progenitor-like cells along with upregulation of the R-spondin/LGR5/RNF43 module. Our results offer a comprehensive description of the molecular basis for pancreatoblastoma and highlight rational therapeutic targets for its treatment.Significance: Molecular genetic analysis of a rare untreatable pediatric tumor reveals Wnt/IGF2 aberrations and features of early pancreas progenitor-like cells, suggesting cellular origins and rational strategies for therapeutic targeting. (C) 2017 AACR.