Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing

Abstract

A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs all revealed the presence of a NAB2-STAT6 gene fusion. Using RT-PCR and sequencing, we detected this fusion in 51 of 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator.

Preclinical and clinical evidence of activity of pazopanib in solitary fibrous tumour

“…Our clinical data, even if retrospective and on a small number of patients, confirm that pazopanib had a modest activity in this sarcoma subtype and, interestingly, are in line with the preclinical results. No RECIST responses could be observed but in one patient the effect of pazopanib was marked by a minor (<30%) decrease in tumour size and by a decrease in tumour density, thus classifying for a PR by Choi criteria [11]. As already described for SFT treated with bevacizumab, sunitinib and sorafenib, Choi criteria [4][5][6][7][8][9], originally conceived for GIST receiving imatinib [11], differed from RECIST in assessing response to therapy.…”

Solitary fibrous tumors: loss of chimeric protein expression and genomic instability mark dedifferentiation

“…The fact that the dedifferentiated variant lacks even this immunophenotypical signature makes its diagnosis particularly challenging because it entirely relies on the presence of a usual/malignant component within the tumor or (in the case of late-recurring pure dedifferentiated tumors) the documentation of a previous solitary fibrous tumor. However, in 2013, whole exome and trancriptome sequencing-based studies 5,6 revealed a chromosomal rearrangement leading to a NAB2/ STAT6 gene fusion that has now been recognized as the hallmark of solitary fibrous tumors on the basis of gene-specific reverse-transcription polymerase chain reaction analyses of solitary fibrous tumor series including usual and malignant variants. [5][6][7][8] NAB2 and STAT6 are contiguous and partially overlapping genes with opposite transcription orientations on chromosome 12q13.3.…”

“…However, in 2013, whole exome and trancriptome sequencing-based studies 5,6 revealed a chromosomal rearrangement leading to a NAB2/ STAT6 gene fusion that has now been recognized as the hallmark of solitary fibrous tumors on the basis of gene-specific reverse-transcription polymerase chain reaction analyses of solitary fibrous tumor series including usual and malignant variants. [5][6][7][8] NAB2 and STAT6 are contiguous and partially overlapping genes with opposite transcription orientations on chromosome 12q13.3. NAB2 is a nuclear protein that acts as a repressor of the transcription induced by some members of the early growth response (EGR) family of transactivators (particularly EGR1) and mediated by interactions with the nucleosome remodeling and deacetylase complex.…”

“…The fusion types NAB2 exon 6/STAT6 exon 17 and NAB2 exon 6/STAT6 exon 18 have recently been associated with malignant behavior, an extrapleural location and a younger age at onset, 8 although this association has not been observed in other studies. 6,7 The discovery of the NAB2/STAT6 fusion made it possible to diagnose solitary fibrous tumor molecularly using reverse-transcription polymerase chain reaction; moreover, the overexpression and phosphorylation-independent nuclear translocation of the STAT6 C-terminus can be readily identified by means of STAT6 immunohistochemistry, a sensitive, specific and more widely available means of accurate diagnosis. 6,10,11 However, although the presence of the NAB2/STAT6 rearrangement is pathognomonic for solitary fibrous tumors, it does not provide any known insights into the biological basis of the spectrum, prognosis or progression of the tumors.…”

“…6,7 The discovery of the NAB2/STAT6 fusion made it possible to diagnose solitary fibrous tumor molecularly using reverse-transcription polymerase chain reaction; moreover, the overexpression and phosphorylation-independent nuclear translocation of the STAT6 C-terminus can be readily identified by means of STAT6 immunohistochemistry, a sensitive, specific and more widely available means of accurate diagnosis. 6,10,11 However, although the presence of the NAB2/STAT6 rearrangement is pathognomonic for solitary fibrous tumors, it does not provide any known insights into the biological basis of the spectrum, prognosis or progression of the tumors. Furthermore, to the best of our knowledge, a solitary fibrous tumor diagnosis has been molecularly confirmed by reverse-transcription polymerase chain reaction in only two dedifferentiated cases.…”