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

NAB2-STAT6融合类型不同是孤立性纤维性肿瘤临床病理不一的原因

Tai HC,Chuang IC,Chen TC,Li CF,Huang SC,Kao YC,Lin PC,Tsai JW,Lan J,Yu SC,Yen SL,Jung SM,Liao KC,Fang FM,Huang HY

Abstract

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 (P<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.

摘要

孤立性纤维性肿瘤(SFT)的特点是12号染色体基因重排(q13q13)-派生出NAB2-STAT6融合,具有不同的断裂点并导致STAT6核表达。不同的NAB2-STAT6融合类型对病理特征和临床行为的影响仍需对SFT进行大规模研究。本文研究了NAB2-STAT6这一基因标记的临床病理联系,并分析了88例SFT(胸内28例、胸外37例、脑膜23例)中STAT6的免疫表达。88例SFTs中75例诊断为非恶性,13例诊断为恶性,其中包括1例去分化SFT。从80例福尔马林固定的标本和/或新鲜样本中提取RNA做RT-PCR检测,73例NAB2-STAT6融合阳性的病例中融合类型包括12个不同的截断点,65例(89%)集中于三个主要的融合类型NAB2外显子4-STAT6外显子2 (33例)为常见的末端受累外显子断裂点,而NAB2外显子6-STAT6外显子16 (16例)和NAB2外显子6-STAT6外显子17(16例)可能显示了不同的断裂点,包含了NAB2或STAT6内含子序列。包括73例融合阳性病例和7例CD34阴性病例在内,共有87例(99%)SFT显示特征性STAT6核阳性表达,其中73例为弥漫阳性,但98例SFT类似肿瘤中未检测到STAT6核表达。7例融合阴性的病例中,6例STAT6显示阳性,提示RT-PCR检测并未涵盖少见的融合类型。不管SFT为哪种组织学亚型,胸内SFT易累及年纪大的患者(P=0.035)且肿瘤体积往往更大(P=0.073)。与其它融合类型相比,NAB2外显子4-STAT6外显子2/4融合更显著见于有以下特点的SFT病例中:位于胸内(P<0.001)、患者年纪大(P=0.005)、核分裂象少(P=0.0028)以及STAT6多灶或弥漫阳性(P=0.013),但未发现该融合类型与无病生存率相关。由此,我们得出结论:STAT6免疫组化核表达在绝大多数SFT中具有独特性,包括所有融合阳性的SFT,可利用该免疫标记诊断CD34阴性的SFT病例。尽管NAB2-STAT6融合类型与几个临床病理因素相关,其预后相关性有待SFT大样本前瞻性研究证实。

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