Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour

Abstract

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm characterised by pathognomonic NAB2-STAT6 gene fusions. The clinical implications and prognostic value of different fusion variants has not been clarified. In the current study, we explore the clinicopathological, prognostic and molecular differences between tumours with different fusions. Thirty-nine patients with localised, extrameningeal SFT were included, of whom 20 developed distant recurrence and 19 were without recurrence after long term follow-up. Capture-based RNA sequencing identified 12 breakpoint variants, which were categorised into two groups based on the STAT6 domain composition in the predicted chimeric proteins. Twenty-one of 34 (62%) sequenced tumours had fusions with most of the STAT6 domains intact and were classified as STAT6-Full. Thirteen tumours (38%) contained only the transactivation domain of STAT6 and were classified as STAT6-TAD. Tumours with STAT6-TAD fusions had a higher mitotic count (p=0.016) and were associated with inferior recurrence-free interval (p=0.004) and overall survival (p=0.012). Estimated 10year recurrence-free survival was 25% for patients with STAT6-TAD tumours compared to 78% for the STAT6-Full group. Distinct transcriptional signatures between the fusion groups were identified, including higher expression of FGF2 in the STAT6-TAD group and IGF2, EGR2, PDGFRB, STAT6 and several extracellular matrix genes in STAT6-Full tumours. In summary, we demonstrate that NAB2-STAT6 fusion variants are associated with distinct clinicopathological and molecular characteristics and have prognostic significance in extrameningeal SFT.

Solitary Fibrous Tumor: Integration of Clinical, Morphologic, Immunohistochemical and Molecular Findings in Risk Stratification and Classification May Better Predict Patient outcome

“…Strong and diffuse nuclear immunoreactivity for STAT6 is a very useful tool for the diagnosis of SFTs, although unexpected epithelial, muscular or neuroendocrine marker expression has also been described in these tumors and may lead to confusion with other neoplasms with hemangiopericytic growth patterns [2,[15][16][17][18][19][20][21][22][23][24][25]33,42]. STAT6 expression has also been reported in dedifferentiated liposarcoma and GLI1-amplified tumors; hence, in cases with overlapping morphology and STAT6 immunoreactivity, additional molecular studies are needed to establish a definitive diagnosis [2,[15][16][17][18][19][20][21][22][23][24][25][33][34][35][36][37][38][39][40][41][42]. Detection of the specific fusion gene NAB2/STAT6 and its variants confirm a diagnosis of SFT, especially in rare clinical settings, unusual histological findings or unexpected immunohistochemical results.…”

“…Detection of the specific fusion gene NAB2/STAT6 and its variants confirm a diagnosis of SFT, especially in rare clinical settings, unusual histological findings or unexpected immunohistochemical results. Moreover, specific gene fusions have been related to prognosis and tumor location [7,8,11,12,[26][27][28][29][30][31][32][35][36][37][38][39][40][41][42]. Various risk-stratification systems (RSS) have been described, with the Demicco et al system being the most widely implemented, as recommended in the World Health Organization (WHO) blue book [1][2][3][4][5]14].…”

“…Molecular studies in SFTs have been progressively implemented in many centers for diagnosis and prognosis. SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax and are less cellular with abundant fibrosis [8][9][10][11][12][28][29][30][31][32][37][38][39][40]. These tumors have a higher tumor age, larger tumor size, lower mitotic activity and lower recurrence rate [28][29][30][31][32][37][38][39][40].…”

“…SFTs with the most common canonical NAB2 exon 4-STAT6 exon 2 fusion variant are often located in the thorax and are less cellular with abundant fibrosis [8][9][10][11][12][28][29][30][31][32][37][38][39][40]. These tumors have a higher tumor age, larger tumor size, lower mitotic activity and lower recurrence rate [28][29][30][31][32][37][38][39][40]. However, those tumors with NAB2 exon 6-STAT6 exon 16/17 fusion variants typically show a more cellular round to ovoid cell morphology and are often located in the deep soft tissue of the intra-abdominal/retroperitoneal/pelvic region or in central nervous system [28][29][30][31][32][37][38][39][40].…”

“…Aberrant epithelial, muscular or neuroendocrine marker expression has been described which may lead to confusion with other tumors that share a similar morphology [15][16][17][18][19][20][21][22][23][24][25]36]. The fusion gene NAB2/STAT6 and its variants confirm a diagnosis of SFT in those cases with unconvincing STAT6 immunoreactivity, and specific gene fusions have been related to prognosis and tumor location [6][7][8][9][10][11][12][13][14][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. STAT6 nuclear expression is not exclusive to SFTs and has also been reported in dedifferentiated liposarcoma, glioma-associated oncogene homolog 1 (GLI1)-amplified tumor, Kaposi sarcoma and Hodgkin as well non-Hodgkin lymphomas [6,[12][13][14][15][16][17][18][19][20]…”