Distinct clinicopathological features of NAB2-STAT6 fusion gene variants in solitary fibrous tumor with emphasis on the acquisition of highly malignant potential

Akaike, Keisuke; Kurisaki-Arakawa, Aiko; Hara, Kieko; Suehara, Yoshiyuki; Takagi, Tatsuya; Mitani, Keiko; Kaneko, Kazuo; Yao, Takashi; Saito, Tsuyoshi

doi:10.1016/j.humpath.2014.11.018

Cited by 118 publications

(153 citation statements)

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“…As summarized in Table 3,~40% (19/48) of cases with informative RT-PCR finings in the series of Barthelmeß lacked information of follow-up durations, and the prognostic comparison for different fusion variants was not evaluated by the ordinary log-rank method. Similar to the series of Akaike et al 18 (Table 3), we could not significantly distinguish between genetic subsets of solitary fibrous tumors with different exon compositions in disease-free survival, leaving the real prognostic impact of NAB2-STAT6 fusion variants undetermined. Admittedly, the desired optimization of RT-PCR in detecting NAB2-STAT6 fusion variants necessitated the extraction of most recently resected formalin-fixed, paraffin-embedded specimens with inherent limitation in the length of follow-up duration and the number of adverse events, which may account for the absence of significant prognostic impact of increased mitoses and malignant histology in our series.…”

Section: Discussionsupporting

confidence: 78%

“…11,13 To make matters complicated, the tremendous variability in both NAB2 and STAT6 breakpoints even exceeded the complexity reported in the EWSR1-FLI1 fusion of Ewing sarcomas 28 and in the FUS-CREB3L1/2 fusions of low-grade fibromyxoid sarcomas, 31 making the delineation of exon compositions in the resultant fusion variants more cumbersome and requiring several RT-PCR assays to cover the less prevalent variants. 11,13,18,19 Given the nuclear entry of STAT6 driven by the NAB2-STAT6 gene fusion, several studies have reported the roles of STAT6 nuclear expression both in authenticating CD34-negative solitary fibrous tumors and in distinguishing solitary fibrous tumors from histological mimics featuring staghorn vasculature and/or CD34 reactivity. 10,20,21 In this study, STAT6 exhibited distinctive nuclear labeling in seven of eight CD34-negative solitary fibrous tumors with typical histology, indicating its better sensitivity.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17] Intriguingly, recent studies revealed significant preponderance of the NAB2ex4-STAT6ex2/3 variants over NAB2ex6-STAT6ex16/17 variants in pleuropulmonary solitary fibrous tumors, and the former were associated with extensive fibrosclerotic stroma, favorable histological variables, and perhaps indolent behavior. 18,19 This finding indicated that determining NAB2-STAT6 exon composition types in solitary fibrous tumors is of potential clinicopathological interest. However, the chimeric NAB2-STAT6 fusion transcript exhibits highly variable breakpoints across 5′ exons of NAB2 and 3' exons of STAT6, hence, rendering reverse transcriptase polymerase chain reaction (RT-PCR) assay more cumbersome to perform using formalinfixed, paraffin-embedded tissue.…”

mentioning

confidence: 90%

“…Following the manufacturers' instructions, 2 μg of total RNA from each fresh or formalin-fixed, paraffin-embedded sample was used to synthesize the first-strand cDNA using ImPromII RT System (Promega). The subsequent PCR was performed by Platinum Taq DNA polymerase (Invitrogen) in a final reaction volume of 25 μl, using 2 μl of cDNA product and newly designed primer sets I to VIII to cover most of the fusion transcripts with various previously reported exon compositions 11,13,18,19 as listed in Supplementary Table S2. The thermal protocol started with 95°C for 5 min for denaturation, followed by 38 cycles of amplification for formalin-fixed, paraffinembedded specimens and 35 cycles for fresh specimens, which consisted of 95°C for 30 s, a touchdown temperature gradient from 62 to 59°C in cycles 1 to 4 and 58°C in the remaining cycles for 30 s, and 72°C for 45 s, and a terminal elongation step of 72°C for 10 min.…”

Section: Rt-pcrmentioning

confidence: 99%

“…However, the chimeric NAB2-STAT6 fusion transcript exhibits highly variable breakpoints across 5′ exons of NAB2 and 3' exons of STAT6, hence, rendering reverse transcriptase polymerase chain reaction (RT-PCR) assay more cumbersome to perform using formalinfixed, paraffin-embedded tissue. 2,[11][12][13]18 As the resultant NAB2-STAT6 fusion protein drives the nuclear entry of STAT6, 11 several groups exploited this biological character of STAT6 nuclear expression to facilitate the discrimination between solitary fibrous tumors and histological mimics, without resorting to RT-PCR. 10,20,21 However, Doyle et al 22 have notified that STAT6 nuclear expression is driven by gene amplification and coamplified with CDK4 and MDM2 in a minor subset of dedifferentiated liposarcomas, a treacherous caveat liable to result in misdiagnosis of solitary fibrous tumors, given occasional presence of solitary fibrous tumorlike histology in dedifferentiated liposarcomas.…”

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confidence: 99%

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NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

et al. 2015

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Solitary fibrous tumor (SFT) is characterized by the inv12(q13q13)-derived NAB2-STAT6 fusion, which exhibits variable breakpoints and drives STAT6 nuclear expression. The implications of NAB2-STAT6 fusion variants in pathological features and clinical behavior remain to be characterized in a large cohort of SFTs. We investigated the clinicopathological correlates of this genetic hallmark and analyzed STAT6 immunoexpression in 28 intrathoracic, 37 extrathoracic, and 23 meningeal SFTs. These 88 tumors were designated as histologically nonmalignant in 75 cases and malignant in 13, including 1 dedifferentiated SFT. Eighty cases had formalin-fixed and/or fresh samples to extract assessable RNAs for RT-PCR assay, which revealed NAB2-STAT6 fusion variants comprising 12 types of junction breakpoints in 73 fusion-positive cases, with 65 (89%) falling into 3 major types. The predominant NAB2ex4-STAT6ex2 (n = 33) showed constant breakpoints at the ends of involved exons, whereas the NAB2ex6-STAT6ex16 (n = 16) and NAB2ex6-STAT6ex17 (n = 16) might exhibit variable breakpoints and incorporate NAB2 or STAT6 intronic sequence. Including 73 fusion-positive and 7 CD34-negative SFTs, STAT6 distinctively labeled 87 (99%) SFTs in nuclei, exhibited diffuse reactivity in 73, but did not decorate 98 mimics tested. In seven fusion-negative cases, 6 were STAT6-positive, suggesting rare fusion variants not covered by RT-PCR assay. Regardless of histological subtypes, intrathoracic SFTs affected older patients (P = 0.035) and tended to be larger in size (P = 0.073). Compared with other variants, NAB2ex4-STAT6ex2/4 fusions were significantly predominant in the SFTs characterised by intrathoracic location (Po 0.001), older age (P = 0.005), decreased mitoses (P = 0.0028), and multifocal or diffuse STAT6 staining (P = 0.013), but not found to correlate with disease-free survival. Conclusively, STAT6 nuclear expression was distinctive in the vast majority of SFTs, including all fusion-positive tumors, and exploitable as a robust diagnostics of CD34-negative cases. Despite the associations of NAB2-STAT6 fusion variants with several clincopathological factors, their prognostic relevance should be further validated in large-scale prospective studies of SFTs.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 90%

Section: Rt-pcrmentioning

confidence: 99%

mentioning

confidence: 99%

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NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

et al. 2015

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The clinicopathological significance of NAB2‐STAT6 gene fusions in 52 cases of intrathoracic solitary fibrous tumors

Huang

Kao

et al. 2015

Cancer Medicine

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NAB2‐STAT6 gene fusion drives STAT6 nuclear expression and is the pathognomonic hallmark of solitary fibrous tumors (SFTs). However, no study has systematically analyzed the clinicopathological features, STAT6 immunoexpression status, or the fusion variants of NAB2‐STAT6 in intrathoracic SFTs. Fifty‐two intrathoracic SFTs were retrieved to appraise histopathology, assess STAT6 immunoexpression, and determine NAB2‐STAT6 fusion variants by RT‐PCR. Location‐relevant histologic mimics served as controls. Thirty‐one pleura‐based, 12 mediastinal/pericardial, and nine intrapulmonary lesions were histologically categorized into eight malignant, eight atypical, and 36 conventional or cellular SFTs, including two fat‐forming and two giant cell angiofibroma‐like SFTs. STAT6 distinctively decorated the tumoral nuclei in 51 (98%) SFTs. However, no nuclear staining was observed in the histological mimics. NAB2‐STAT6 fusion was detected in 34 SFTs. Twenty‐nine (85.3%) exhibited the major NAB2ex4‐STAT6ex2/3 variant and 5 (14.7%) the minor NAB2ex6‐STAT6ex16/17. NAB2ex4‐STAT6ex2 was significantly associated with older age (P = 0.01) and pleuropulmonary tumors (P = 0.025). After a median follow‐up of 33.9 (range, 0.3–174.6) months, adverse outcomes occurred in one atypical and five malignant SFTs, including two local relapses, one intrapulmonary metastasis, and three extrathoracic metastases. Inferior disease‐free survival was univariately associated with atypical/malignant histology (P = 0.001) and a mitosis >4/10 HPFs (P = 0.0012) but was unrelated to fusion variants. In conclusion, the majority of intrathoracic SFTs exhibited STAT6 nuclear staining, and NAB2ex4‐STAT6ex2/3 was the predominant fusion type. However, clinical aggressiveness is associated with atypical/malignant histology primarily contributed by increased mitosis but was unrelated to the NAB2‐STAT6 fusion variants.

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Molecular testing of soft tissue tumors

Rottmann

Abdulfatah

Pantanowitz

2022

Diagnostic Cytopathology

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Background: The diagnosis of soft tissue tumors is challenging, especially when the evaluable material procured is limited. As a result, diagnostic ancillary testing is frequently needed. Moreover, there is a trend in soft tissue pathology toward increasing use of molecular results for tumor classification and prognostication. Hence, diagnosing newer tumor entities such as CIC-rearranged sarcoma explicitly requires molecular testing. Molecular testing can be accomplished by in situ hybridization, polymerase chain reaction, as well as next generation sequencing, and more recently such testing can even be accomplished leveraging an immunohistochemical proxy. Conclusion:This review evaluates the role of different molecular tests in characterizing soft tissue tumors belonging to various cytomorphologic categories that have been sampled by small biopsy and cytologic techniques.

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Distinct clinicopathological features of NAB2-STAT6 fusion gene variants in solitary fibrous tumor with emphasis on the acquisition of highly malignant potential

Cited by 118 publications

References 33 publications

NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

NAB2–STAT6 fusion types account for clinicopathological variations in solitary fibrous tumors

The clinicopathological significance of NAB2‐STAT6 gene fusions in 52 cases of intrathoracic solitary fibrous tumors

Molecular testing of soft tissue tumors

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