Agaram Narasimhan P, Sung Yun-Shao, Zhang Lei, Chen Chun-Liang, Chen Hsiao-Wei, Singer Samuel, Dickson Mark A, Berger Michael F, Antonescu Cristina R
Departments of *Pathology †Surgery §Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center ‡Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.
Am J Surg Pathol. 2015 Jun;39(6):813-25. doi: 10.1097/PAS.0000000000000389.
Perivascular epithelioid cell neoplasms (PEComa) are a family of rare mesenchymal tumors with hybrid myo-melanocytic differentiation. Although most PEComas harbor loss-of-function TSC1/TSC2 mutations, a small subset were reported to carry TFE3 gene rearrangements. As no comprehensive genomic study has addressed the molecular classification of PEComa, we sought to investigate by multiple methodologies the incidence and spectrum of genetic abnormalities and their potential genotype-phenotype correlations in a large group of 38 PEComas. The tumors were located in soft tissue (11 cases) and visceral sites (27) including uterus, kidney, liver, lung, and urinary bladder. Combined RNA sequencing and fluorescence in situ hybridization analysis identified 9 (23%) TFE3 gene-rearranged tumors, with 3 cases showing an SFPQ/PSF-TFE3 fusion and 1 case showing a novel DVL2-TFE3 gene fusion. The TFE3-positive lesions showed a distinctive nested/alveolar morphology and were equally distributed between soft tissue and visceral sites. In addition, novel RAD51B gene rearrangements were identified in 3 (8%) uterine PEComas, which showed a complex fusion pattern and were fused to RRAGB/OPHN1 genes in 2 cases. Other nonrecurrent gene fusions, HTR4-ST3GAL1 and RASSF1-PDZRN3, were identified in 2 cases. Targeted exome sequencing using the IMPACT assay was used to address whether the presence of gene fusions is mutually exclusive from TSC gene abnormalities. TSC2 mutations were identified in 80% of the TFE3 fusion-negative cases tested. Coexistent TP53 mutations were identified in 63% of the TSC2-mutated PEComas. Our results showed that TFE3-rearranged PEComas lacked coexisting TSC2 mutations, indicating alternative pathways of tumorigenesis. In summary, this comprehensive genetic analysis significantly expands our understanding of molecular alterations in PEComas and brings forth the genetic heterogeneity of these tumors.
血管周上皮样细胞瘤（PEComa）是一类罕见的间充质肿瘤，具有肌样-黑素细胞混合分化特征。尽管大多数PEComa存在功能丧失的TSC1/TSC2突变，但据报道一小部分携带TFE3基因重排。由于尚无全面的基因组研究涉及PEComa的分子分类，我们试图通过多种方法研究38例大量PEComa中基因异常的发生率和谱系及其潜在的基因型-表型相关性。肿瘤位于软组织（11例）和内脏部位（27例），包括子宫、肾脏、肝脏、肺和膀胱。联合RNA测序和荧光原位杂交分析鉴定出9例（23%）TFE3基因重排肿瘤，其中3例显示SFPQ/PSF-TFE3融合，1例显示新的DVL2-TFE3基因融合。TFE3阳性病变表现出独特的巢状/腺泡状形态，在软组织和内脏部位分布均匀。此外，在3例（8%）子宫PEComa中鉴定出新的RAD51B基因重排，其显示复杂的融合模式，2例与RRAGB/OPHN1基因融合。在2例中鉴定出其他非复发性基因融合，即HTR4-ST3GAL1和RASSF1-PDZRN3。使用IMPACT检测进行靶向外显子组测序，以探讨基因融合的存在是否与TSC基因异常相互排斥。在80%检测的TFE3融合阴性病例中鉴定出TSC2突变。在63%的TSC2突变的PEComa中鉴定出共存的TP53突变。我们的结果表明，TFE3重排的PEComa缺乏共存的TSC2突变，表明存在替代的肿瘤发生途径。总之，这项全面的基因分析显著扩展了我们对PEComa分子改变的理解，并揭示了这些肿瘤的基因异质性。
