Perivascular Epithelioid Cell Tumors (PEComas) Harboring TFE3 Gene Rearrangements Lack the TSC2 Alterations Characteristic of Conventional PEComas: Further Evidence for a Biological Distinction

*Brigham & Women's Hospital Boston, MA †Department of Pathology, Emory University, Atlanta, GA ‡Department of Pathology, University of Verona, Verona, Italy §The Johns Hopkins Hospital Baltimore, MD.
The American journal of surgical pathology (Impact Factor: 4.59). 03/2012; 36(5):783-4. DOI: 10.1097/PAS.0b013e31824a8a37
Source: PubMed


Available from: Izabela Malinowska, Jun 03, 2015
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    ABSTRACT: 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.
    American Journal of Surgical Pathology 02/2015; 39(6). DOI:10.1097/PAS.0000000000000389 · 4.59 Impact Factor
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    ABSTRACT: Tuberous Sclerosis Complex (TSC) is a genetic disorder characterized by seizures and tumor formation in multiple organs, mainly in the brain, skin, kidney, lung and heart. Renal Cell Carcinoma (RCC) occurs in about 3% of TSC patients, and typically develops at age<50. Here we describe genetic findings in two TSC patients with multiple renal tumors, each of whom had the germline mutation TSC2 p.R905Q. The first (female) TSC patient had a left followed by a right nephrectomy at ages 24 and 27. Both kidneys showed multifocal TSC-associated papillary RCC (PRCC). Targeted, next-generation sequencing (NGS) analysis of TSC2 in five tumors (4 from the left kidney, 1 from the right) showed LOH in one tumor, and four different TSC2 point mutations (p.E1351*, p.R1032*, p.R1713H, c.4178_4179delCT) in the other four samples. Only one of the 11 other tumors available from this patient had one of the TSC2 second hit mutations identified. Whole exome analysis of the five tumors identified a very small number of additional mutated genes, with an average of 3.4 nonsilent coding, somatic mutations per tumor, none of which were seen in>1 tumor. The second (male) TSC patient had bilateral partial nephrectomies (both at age 36), with similar findings of multifocal PRCC. NGS analysis of TSC2 in two of these tumors identified a second hit mutation c.2355+1G>T in one sample that was not seen in other tumors. In conclusion, we report the first detailed genetic analysis of RCCs in TSC patients. Molecular studies indicate that tumors developed independently due to various second hit events, suggesting that these patients experienced a 'shower' of second hit mutations in TSC2 during kidney development leading to this severe phenotype. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email:
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    ABSTRACT: PEComas are mesenchymal tumors composed of histologically and immunohistochemically distinctive perivascular epithelioid cells which are characterized by the coexpression of muscle and melanogenesis markers. This group of lesions includes angiomyolipoma, clear-cell “sugar” tumor of the lung and extrapulmonary sites, lymphangioleiomyomatosis, clear-cell myomelanocytic tumor of the falciform ligament/ligamentum teres and rare clear-cell tumors of other anatomical sites. In the genitourinary tract PEComas have been described in the kidney, bladder, prostate, testis and urethra. Although most PEComas behave as benign tumors, some are potentially malignant and criteria for malignancy have been suggested for both and renal and extrarenal lesions. Recently the expression of cathepsin K has been demonstrated in a large number of PEComas and has been proposed as a relatively specific marker to distinguish these proliferations from the majority of human cancers. In addition, a distinctive subset of PEComas harboring TFE3 gene fusions have been reported, giving rise to a possible relationship between them and MiTF/TFE family translocation renal cell carcinomas. The genetic alterations of tuberous sclerosis complex that promote activation of the mTOR pathway have been identified in PEComas. Therapy with mTORC1 inhibitors has been shown to be effective in some cases.
    Seminars in Diagnostic Pathology 02/2015; 32(2). DOI:10.1053/j.semdp.2015.02.006 · 1.80 Impact Factor