High-density genome-wide copy number variation (CNV) in human head and neck paragangliomas.. Homo sapiens

Gene-centric CNV analysis of 24 individual paraganglioma cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The NOTCH signaling pathway was the most significantly enriched term in the list. Overexpression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunomorphological studies in 47 paragangliomas, including CNV-tested cases. NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of the pathway. Notably, this was confirmed by microRNA expression analysis, that showed tumor-associated downregulation of the miR-200s and miR-34s families, correlated to NOTCH signaling and directly targeting NOTCH1. Overall design: Total DNA from paraganglioma sample compared to total DNA from paired blood sample.

对24例副神经节瘤病例开展以基因为中心的拷贝数变异（CNV）分析，鉴定出104个最易受肿瘤相关变异靶向的核心基因。NOTCH信号通路是该基因列表中富集程度最高的功能术语。针对47例副神经节瘤（含经CNV检测的病例）开展的免疫形态学研究证实，相关NOTCH通路蛋白在支持细胞（胶质细胞）、主细胞（神经内分泌细胞）及内皮细胞中呈过表达状态。在未检测到NOTCH信号通路基因存在CNV的病例中，同样观察到NOTCH通路上调现象，提示该通路存在表观遗传调控异常。值得注意的是，这一结论经微小RNA（microRNA）表达分析得到验证：该分析显示肿瘤相关的miR-200家族与miR-34家族表达下调，这两类microRNA与NOTCH信号通路相关且可直接靶向NOTCH1基因。实验整体设计：将副神经节瘤样本的总DNA与配对血液样本的总DNA进行比对分析。