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Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK gene rearrangements
Journal of Thoracic Oncology ( IF 20.4 ) Pub Date : 2019-05-01 , DOI: 10.1016/j.jtho.2018.12.003
Jason C Chang 1 , Lei Zhang 1 , Alexander E Drilon 2 , Ping Chi 3 , Rita Alaggio 4 , Laetitia Borsu 1 , Ryma Benayed 1 , William D Travis 1 , Marc Ladanyi 5 , Cristina R Antonescu 1
Affiliation  

Introduction: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next‐generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK‐negative IMTs. Methods: In this study, we have investigated a series of pediatric and adult thoracic IMTs for abnormalities in a wide spectrum of actionable kinases by applying a variety of molecular and next‐generation sequencing techniques, including fluorescence in situ hybridization (FISH), targeted RNA sequencing, and NanoString assay. Results: There were 33 patients with thoracic IMTs, including five children; their mean age was 37. The tumors showed a monomorphic spindle cell phenotype, except for one with an epithelioid morphologic pattern and moderate to severe atypia. By immunohistochemistry, 24 tumors were ALK positive, and 19 of the 24 showed ALK rearrangements and one ret proto‐oncogene gene (RET) rearrangement by FISH. RNA sequencing was performed in the remaining four cases lacking ALK abnormalities by FISH, revealing ALK fusions involving tropomyosin 4 gene (TMP4) and echinoderm microtubule associated protein like 4 gene (EML4) as partner in three cases. NanoString assay was performed in the remaining case, revealing ALK alternative transcription initiation (ALKATI). Nine cases lacking ALK abnormalities were further tested by FISH or targeted RNA sequencing, revealing ROS1 rearrangement in six cases and ETS variant 6 gene (ETV6)–neurotrophic receptor tyrosine kinase 3 gene (NTRK3) fusion in three cases, respectively. Conclusions: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI‐induced ALK oncogenic activation in IMTs.

中文翻译:

扩大胸腔炎性肌纤维母细胞肿瘤的分子特征,超越 ALK 基因重排

简介:无论解剖位置如何,一半的炎性肌纤维母细胞肿瘤 (IMT) 都具有间变性淋巴瘤激酶基因 (ALK) 重排和过度表达间变性淋巴瘤激酶蛋白。二代测序的广泛应用和酪氨酸激酶抑制剂的临床益处为研究 ALK 阴性 IMT 开辟了新的机会。方法:在这项研究中,我们通过应用各种分子和下一代测序技术,包括荧光原位杂交 (FISH)、靶向 RNA测序和 NanoString 分析。结果:胸椎IMT患者33例,其中儿童5例;他们的平均年龄是 37 岁。除了具有上皮样形态学模式和中度至重度异型性的肿瘤外,肿瘤显示出单形梭形细胞表型。免疫组化显示24个肿瘤为ALK阳性,24个肿瘤中有19个显示ALK重排,FISH显示1个ret原癌基因(RET)重排。通过 FISH 对其余 4 例缺乏 ALK 异常的病例进行 RNA 测序,揭示 ALK 融合涉及原肌球蛋白 4 基因(TMP4)和棘皮动物微管相关蛋白如 4 基因(EML4)作为伴侣的 3 例。NanoString 测定在其余情况下进行,揭示了 ALK 替代转录起始 (ALKATI)。通过 FISH 或靶向 RNA 测序进一步检测了 9 例缺乏 ALK 异常的病例,分别显示 6 例 ROS1 重排和 3 例 ETS 变异 6 基因(ETV6)-神经营养受体酪氨酸激酶 3 基因(NTRK3)融合。结论:通过使用一系列互补分子技术,我们发现所有胸部 IMT 都存在酪氨酸激酶异常,其中 30% 涉及 ALK 以外的激酶基因,包括 ROS1、NTRK3 和 RET 基因融合。我们还首次描述了 IMT 中 ALKATI 诱导的 ALK 致癌激活。
更新日期:2019-05-01
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