Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, NY.
Genes Chromosomes Cancer. 2013 Nov;52(11):1075-87. doi: 10.1002/gcc.22102. Epub 2013 Sep 2.
Glomus tumors (GT) have been classified among tumors of perivascular smooth muscle differentiation, together with myopericytoma, myofibroma/tosis, and angioleiomyoma, based on their morphologic overlap. However, no molecular studies have been carried out to date to investigate their genetic phenotype and to confirm their shared pathogenesis. RNA sequencing was performed in three index cases (GT1, malignant GT; GT2, benign GT and M1, multifocal myopericytoma), followed by FusionSeq data analysis, a modular computational tool developed to discover gene fusions from paired-end RNA-seq data. A gene fusion involving MIR143 in band 5q32 was identified in both GTs with either NOTCH2 in 1p13 in GT1 or NOTCH1 in 9q34 in GT2, but none in M1. After being validated by FISH and RT-PCR, these abnormalities were screened on 33 GTs, 6 myopericytomas, 9 myofibroma/toses, 18 angioleiomyomas and in a control group of 5 sino-nasal hemangiopericytomas. Overall NOTCH2 gene rearrangements were identified in 52% of GT, including all malignant cases and one NF1-related GT. No additional cases showed NOTCH1 rearrangement. As NOTCH3 shares similar functions with NOTCH2 in regulating vascular smooth muscle development, the study group was also investigated for abnormalities in this gene by FISH. Indeed, NOTCH3 rearrangements were identified in 9% of GTs, all present in benign soft tissue GT, one case being fused to MIR143. Only 1/18 angioleiomyomas showed NOTCH2 gene rearrangement, while all the myopericytomas and myofibroma/toses were negative. In summary, we describe novel NOTCH1-3 rearrangements in benign and malignant, visceral, and soft tissue GTs.
血管周平滑肌肿瘤（GT）与肌上皮瘤、肌纤维瘤/瘤病和血管平滑肌脂肪瘤一起，基于其形态学重叠，被归类为血管周平滑肌分化的肿瘤。然而，迄今为止，尚未进行任何分子研究来研究其遗传表型并确认其共同的发病机制。在三个索引病例（GT1，恶性 GT；GT2，良性 GT 和 M1，多灶性肌上皮瘤）中进行了 RNA 测序，随后进行了 FusionSeq 数据分析，这是一种用于从配对末端 RNA-seq 数据中发现基因融合的模块化计算工具。在两个 GT 中都发现了涉及 5q32 上的 MIR143 的基因融合，一个在 GT1 中涉及 1p13 上的 NOTCH2，另一个在 GT2 中涉及 9q34 上的 NOTCH1，但在 M1 中没有。在通过 FISH 和 RT-PCR 验证后，在 33 个 GT、6 个肌上皮瘤、9 个肌纤维瘤/瘤病、18 个血管平滑肌脂肪瘤和 5 个鼻-鼻窦血管外皮细胞瘤的对照组中筛选了这些异常。总体而言，在 52%的 GT 中发现了 NOTCH2 基因重排，包括所有恶性病例和一个与 NF1 相关的 GT。没有其他病例显示 NOTCH1 重排。由于 NOTCH3 在调节血管平滑肌发育方面与 NOTCH2 具有相似的功能，因此研究组还通过 FISH 研究了该基因的异常。事实上，在 9%的 GT 中发现了 NOTCH3 重排，所有这些重排都存在于良性软组织 GT 中，一个病例与 MIR143 融合。只有 1/18 的血管平滑肌脂肪瘤显示 NOTCH2 基因重排，而所有的肌上皮瘤和肌纤维瘤/瘤病均为阴性。总之，我们描述了良性和恶性、内脏和软组织 GT 中新型的 NOTCH1-3 重排。
