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Surgical therapy and next-generation sequencing-based genetic alteration analysis of malignant solitary fibrous tumor of the pleura.

ABSTRACT: Background:Solitary fibrous tumor of the pleura (SFTP) is a rare pleural neoplasm arising from mesenchymal cells, accounting for <5% of pleural neoplasms. Approximately 10% of cases of SFTP demonstrate malignant potential, leading to local recurrence after radical surgery and subsequent metastasis. Methods:A large malignant-like mass was found in the left thoracic cavity of a 61-year-old woman. Following radical resection of the mass, the patient was diagnosed with malignant SFTP by histologic and immunohistochemical analyses. In addition, a next-generation sequencing-based mutation test was used to reveal the mutational profile of the tumor. The genetic alteration panel was analyzed with reference to public data on the ClinVar and COSMIC databases, after which the public SFTP data were analyzed for frequency of altered genes. Finally, through overlay of the abovementioned two sets, the genetic alteration accounting for SFTP initiation was anticipated to be identified. Results:In the mutation panel of our malignant SFTP group, kinase insert domain receptor (KDR) and fms-related tyrosine kinase 1 (FLT1) scored high in pathogenesis but had only a medium frequency; the NAB2-STAT6 fusion appeared to be the dominant genetic alteration in public SFTP samples. Conclusion:The high frequency of NAB2-STAT6 fusion indicates its prominent role in SFTP, while somatic mutations such as FLT1-R593W and KDR-V297I may also contribute to the malignant angiogenic phenotype. The present study affirmed the heterogeneity of SFTP, and more sophisticated classification methods will be needed to explore its underlying mechanisms. Summary:We believe that improvement in the prognosis of SFTP relies on early diagnosis, margin-free resection, and long-term follow-up. Through genetic analysis, it appears that both NAB2-STAT6 fusion and somatic mutations such as FLT1-R593W and KDR-V297I contribute to SFTP development.

SUBMITTER: Song Z

PROVIDER: S-EPMC6118252 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Surgical therapy and next-generation sequencing-based genetic alteration analysis of malignant solitary fibrous tumor of the pleura.

Song Zuoqing Z Yang Fan F Zhang Yingguo Y Fan Ping P Liu Guowei G Li Chao C Ding Wansheng W Zhang Yulong Y Xu Xiaohong X Ye Yancheng Y

OncoTargets and therapy 20180828

<h4>Background</h4>Solitary fibrous tumor of the pleura (SFTP) is a rare pleural neoplasm arising from mesenchymal cells, accounting for <5% of pleural neoplasms. Approximately 10% of cases of SFTP demonstrate malignant potential, leading to local recurrence after radical surgery and subsequent metastasis.<h4>Methods</h4>A large malignant-like mass was found in the left thoracic cavity of a 61-year-old woman. Following radical resection of the mass, the patient was diagnosed with malignant SFTP ...[more]

PMID: 30214228

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Project description: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.

Dataset Information

Surgical therapy and next-generation sequencing-based genetic alteration analysis of malignant solitary fibrous tumor of the pleura.

Publications

Surgical therapy and next-generation sequencing-based genetic alteration analysis of malignant solitary fibrous tumor of the pleura.

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