Comprehensive Genetic Analysis Identifies a Pathognomonic NAB2/STAT6 Fusion Gene, Nonrandom Secondary Genomic Imbalances, and a Characteristic Gene Expression Profile in Solitary Fibrous Tumor
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Date
2013
Journal Title
Journal ISSN
Volume Title
Publisher
Genes, Chromosomes and Cancer
Abstract
Solitary fibrous tumor (SFT) is a mesenchymal neoplasm displaying variable morphologic and clinical features. To identify
pathogenetically important genetic rearrangements, 44 SFTs were analyzed using a variety of techniques. Chromosome
banding and fluorescence in situ hybridization (FISH) showed recurrent breakpoints in 12q13, clustering near the NAB2
and STAT6 genes, and single nucleotide polymorphism array analysis disclosed frequent deletions affecting STAT6. Quantitative
real-time PCR revealed high expression levels of the 5’-end of NAB2 and the 3’-end of STAT6, which at deep sequencing
of enriched DNA corresponded to NAB2/STAT6 fusions. Subsequent reverse-transcriptase PCR (RT-PCR) analysis
identified a NAB2/STAT6 fusion in 37/41 cases, confirming that this fusion gene underlies the pathogenesis of SFT. The
hypothesis that the NAB2/STAT6 fusions will result in altered properties of the transcriptional co-repressor NAB2 - a key
regulator of the early growth response 1 (EGR1) transcription factor – was corroborated by global gene expression analysis;
SFTs showed deregulated expression of EGR1 target genes, as well as of other, developmentally important genes. We
also identified several nonrandom secondary changes, notably loss of material from 13q and 14q. As neither chromosome
banding nor FISH analysis identify more than a minor fraction of the fusion-positive cases, and because multiple primer
combinations are required to identify all possible fusion transcripts by RT-PCR, alternative diagnostic markers might instead
be found among deregulated genes identified at global gene expression analysis. Indeed, using immunohistochemistry
on tissue microarrays, the top up-regulated gene, GRIA2, was found to be differentially expressed also at the protein level.
Description
Keywords
Genetic Analysis, Pathognomonic NAB2/STAT6 Fusion Gene, Genomic Imbalances, Gene Expression Profile, Solitary Fibrous Tumor
Citation
Mohajeri, A., Tayebwa, J., Collin, A., Nilsson, J., Magnusson, L., von Steyern, F. V., ... & Mertens, F. (2013). Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor. Genes, Chromosomes and Cancer, 52(10), 873-886. DOI 10.1002/gcc.22083