Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications. (June 2015)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: American journal of surgical pathology. Volume 39:Number 6(2015)
• Publication Date: 2015-06
• Subjects: Pathology, Surgical -- Periodicals; 617.0705
• DOI: 10.1097/PAS.0000000000000389
• Languages: English
• ISSNs: 0147-5185

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <p>Perivascular epithelioid cell neoplasms (PEComa) are a family of rare mesenchymal tumors with hybrid myo-melanocytic differentiation. Although most PEComas harbor loss-of-function <italic>TSC1/TSC2</italic> mutations, a small subset were reported to carry <italic>TFE3</italic> 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%) <italic>TFE3</italic> gene–rearranged tumors, with 3 cases showing an <italic>SFPQ/PSF-TFE3</italic> fusion and 1 case showing a novel <italic>DVL2-TFE3</italic> gene fusion. The <italic>TFE3</italic>-positive lesions showed a distinctive nested/alveolar morphology and were equally distributed between soft tissue and visceral sites. In addition, novel <italic>RAD51B</italic> gene rearrangements were identified in 3 (8%) uterine PEComas, which showed a complex fusion pattern and were fused to <italic>RRAGB/OPHN1</italic> genes in 2 cases. Other nonrecurrent gene fusions, <italic>HTR4-ST3GAL1</italic> and <italic>RASSF1-PDZRN3</italic>, 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 <italic>TSC</italic> gene abnormalities. <italic>TSC2</italic> mutations were identified in 80% of the <italic>TFE3</italic> fusion-negative cases tested. Coexistent <italic>TP53</italic> mutations were identified in 63% of the <italic>TSC2</italic>-mutated PEComas. Our results showed that <italic>TFE3</italic>-rearranged PEComas lacked coexisting <italic>TSC2</italic> 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.</p> </sec> </abstract>