Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

6533b7dbfe1ef96bd127149a

RESEARCH PRODUCT

Hypoxia-Inducible Factor 2α Mutation-Related Paragangliomas Classify as Discrete Pseudohypoxic Subcluster

W. Marston Linehan Jan Breza Jürgen Brieger Zhengping Zhuang Graeme Eisenhofer Roland Daerr Roland Daerr Uma Shankavaram Hendrik Lehnert Henri J L M Timmers Karel Pacak Ronald R. De Krijger Konstantinos Papaspyrou Stephanie M. J. Fliedner Stephanie M. J. Fliedner Geena Marzouca Arthur S. Tischler Abdel G. Elkahloun Ivana Jochmanova

subject

Adult Male 0301 basic medicine Original article Cancer Research Adolescent Microarray SDHB SDHA Biology lcsh:RC254-282 Oxidative Phosphorylation Paraganglioma Young Adult 03 medical and health sciences 0302 clinical medicine Paraganglioma Basic Helix-Loop-Helix Transcription Factors medicine Journal Article Cluster Analysis Humans Child Hypoxia Aged Genetics Gene Expression Profiling Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16]Middle Aged lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease Phenotype Gene Expression Regulation Neoplastic Gene expression profiling 030104 developmental biology Hypoxia-inducible factors 030220 oncology & carcinogenesis Mutation Female SDHD Transcriptome Protein Binding

description

Contains fulltext : 172720.pdf (Publisher’s version ) (Open Access) Recently, activating mutations of the hypoxia-inducible factor 2alpha gene (HIF2A/EPAS1) have been recognized to predispose to multiple paragangliomas (PGLs) and duodenal somatostatinomas associated with polycythemia, and ocular abnormalities. Previously, mutations in the SDHA/B/C/D, SDHAF2, VHL, FH, PHD1, and PHD2 genes have been associated with HIF activation and the development of pseudohypoxic (cluster-1) PGLs. These tumors overlap in terms of tumor location, syndromic presentation, and noradrenergic phenotype to a certain extent. However, they also differ especially by clinical outcome and by presence of other tumors or abnormalities. In the present study, we aimed to establish additional molecular differences between HIF2A and non-HIF2A pseudohypoxic PGLs. RNA expression patterns of HIF2A PGLs (n=6) from 2 patients were compared with normal adrenal medullas (n=8) and other hereditary pseudohypoxic PGLs (VHL: n=13, SDHB: n=15, and SDHD: n=14). Unsupervised hierarchical clustering showed that HIF2A PGLs made up a separate cluster from other pseudohypoxic PGLs. Significance analysis of microarray yielded 875 differentially expressed genes between HIF2A and other pseudohypoxic PGLs after normalization to adrenal medulla (false discovery rate 0.01). Prediction analysis of microarray allowed correct classification of all HIF2A samples based on as little as three genes (TRHDE, LRRC63, IGSF10; error rate: 0.02). Genes with the highest expression difference between normal medulla and HIF2A PGLs were selected for confirmatory quantitative reverse transcriptase polymerase chain reaction. In conclusion, HIF2A PGLs show a characteristic expression signature that separates them from non-HIF2A pseudohypoxic PGLs. Unexpectedly, the most significantly differentially expressed genes have not been previously described as HIF target genes.

year	journal	country	edition	language
2016-09-01	Neoplasia

10.1016/j.neo.2016.07.008 https://doi.org/10.1016/j.neo.2016.07.008