Molecular changes in solitary fibrous tumor progression

Abstract

Solitary fibrous tumors (SFTs) are NAB2-STAT6 fusion-associated neoplasms. There are several subtypes of NAB2-STAT6 fusions, but their clinical significances are still unclear. Moreover, the mechanisms of malignant progression are also poorly understood. In this study, using 91 SFT cases, we examined whether fusion variants are associated with clinicopathological parameters and also investigated the molecular mechanism of malignant transformation using whole-exome sequencing. We detected variant 1b (NAB2ex4-STAT6ex2) in 51/91 (56%) cases and variants 2a/2b (NAB2ex6-STAT6ex16/17) in 17/91 (19%) cases. The NAB2-STAT6 fusion variant types were significantly associated with their primary site (P < 0.001). In addition, a TERT promoter mutation was detected in 7/73 (10%) cases, and it showed a significant association with malignant SFTs (P = 0.003). To identify molecular changes during malignant progression, we selected an index patient to obtain parallel tissue samples from the primary and metastatic tumors. In the metastatic tissue, 10 unique molecular alterations, including those in TP53 and APAF1, were detected. In vitro functional experiments showed that APAF1 depletion increased the tumor potency of cells expressing NAB2-STAT6 fusion protein under treatment with staurosporine. We found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs. Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation.Key messages We firstly found that the TERT promoter mutation was strongly associated with malignant SFTs (P = 0.003) and the representative 1b (NAB2ex4-STAT6ex2) or 2a (NAB2ex6-STAT6ex16) fusion variants similarly contribute to tumorigenicity.We also found that TP53 immunopositivity (P = 0.006) and loss of APAF1 immunoreactivity (P < 0.001) were significantly associated with malignant SFTs.Our study suggests that dysfunction of TP53 and APAF1 leads to impaired apoptotic function, and eventually contributes toward malignant SFT transformation. Electronic supplementary materialThe online version of this article (10.1007/s00109-019-01815-8) contains supplementary material, which is available to authorized users.

Controversial issues in soft tissue solitary fibrous tumors: A pathological and molecular review

“…In contrast, another group of SFT evolved favorably, despite having a similar size, location or other parameters associated with aggressive behavior . This emphasizes the unpredictability of these systems for risk stratification, and supports the idea that additional biological or molecular factors potentially influence the evolution of SFT . We consider that while certain histological parameters are frequently associated with malignant behavior, using these criteria alone to label an SFT as benign or malignant at diagnosis may be unreliable.…”

“…Many SFT behave in a benign fashion, nevertheless, up to 40% of cases may follow an aggressive course with metastases or late relapsed disease . Numerous risk models have been proposed, unfortunately they do not accurately predict clinical evolution, probably due to variations in the cohort and the relatively short follow‐up periods in the reported series .…”

“…Many of the histological variants reveal a focal patternless architecture, and variably fibro‐collagenous stroma . NAB2‐STAT6 was discovered as a novel fusion gene of SFTs, and STAT6 immunoexpression has been established as a surrogate marker of the NAB2‐STAT6 gene fusion, expression of this protein representing a very sensitive and specific diagnostic tool …”

“…Although several publications have discussed the histological, clinical or molecular criteria for malignancy in SFT, no feasible determinant of malignancy has yet been established for practical use . This situation has prompted the creation of several risk stratification systems, incorporating not only histological factors, but also clinical or radiological parameters . Nevertheless, few studies have evaluated the role of molecular alterations in malignant SFTs compared to nonmalignant SFTs .…”

“…) or anaplastic component . Dedifferentiation may be de novo or secondary during recurrence or progression of classic SFT and may be associated with lost or decreased immunoexpression of some typical SFT markers (CD34 and STAT6), while usually new genetic disorders such as p53 alterations are acquired . Dedifferentiation is generally associated with malignancy; however, metastatic or malignant SFT may not necessarily demonstrate dedifferentiation in the primary tumor .…”