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

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. Total DNA from paraganglioma sample compared to total DNA from paired blood sample.