Dichotomy of Genetic Abnormalities in PEComas With Therapeutic Implications

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 (FISH) analysis identified 9 (23%) TFE3 gene rearranged tumors, with 3 cases showing a SFPQ/PSF-TFE3 fusion and one case 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. Additionally, 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 two cases. Other non-recurrent gene fusions, HTR4-ST3GAL1 and RASSF1-PDZRN3, were identified in 2 cases. Targeted exome sequencing using the IMPACT assay was used to address if the presence of gene fusions are mutually exclusive from TSC gene abnormalities. TSC2 mutations were identified in 80% of the TFE3 fusion-negative cases tested. Co-existent TP53 mutations were identified in 63% of the TSC2 mutated PEComas. Our results showed that TFE3-rearranged PEComas lacked co-existing 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.

Giant Perivascular Epithelioid Cell Tumor of the Orbit: A Clinicopathological Analysis and Review of the Literature

“…These genes relate to enzymes involved in catecholamine metabolism and melanin formation [4, 27]. Rearrangements on the TFE3 gene have also been recently reported in PEComas [28]. However, these changes that eventually lead to cell growth and proliferation have been studied in TSC-associated renal tumors, sporadic AML, LAM, and also multifocal micronodular pneumocyte hyperplasia.…”

Predicting the Behavior of Perivascular Epithelioid Cell Tumors of the Uterine Corpus

“…10 Although only 1 of the 9 neoplasms that showed a TFE3 translocation originated in the uterus, translocations involving RAD51 were identified exclusively in uterine PEComas. 10 Interestingly, TSC2 mutations seemed to be mutually exclusive with TFE3 translocations, because only TFE3 translocationnegative PEComas showed TSC2 mutations and vice versa. 10 Also, 5 of 8 translocation-negative/TSC2-mutated PEComas showed synchronous mutations of TP53 (tumor protein 53).…”

“…10 Interestingly, TSC2 mutations seemed to be mutually exclusive with TFE3 translocations, because only TFE3 translocationnegative PEComas showed TSC2 mutations and vice versa. 10 Also, 5 of 8 translocation-negative/TSC2-mutated PEComas showed synchronous mutations of TP53 (tumor protein 53). 10 Authors 12 from the University of Pennsylvania demonstrated increased expression of TP53 by immunohistochemistry in pure epithelioid PEComa, compared with conventional angiomyolipoma.…”

“…8 Mutations of TSC2 have been described in 62% of PEComas overall and in 80% of the PEComa subgroup lacking translocations of the TFE3 gene, as described below. 10 Recently, a study 10 of 38 PEComas found that 9 (23%) of them harbored translocations of TFE3 (transcription factor E3), a member of the microphthalmia transcription factor (MiTF) gene family located in the short arm of chromosome X. Although the function of the MiTF gene family members as inducers of melanocyte differentiation is well established, providing an elegant explanation for the dual phenotype of PEComas, their mechanistic role in tumorigenesis is still controversial.…”

“…10 Also, 5 of 8 translocation-negative/TSC2-mutated PEComas showed synchronous mutations of TP53 (tumor protein 53). 10 Authors 12 from the University of Pennsylvania demonstrated increased expression of TP53 by immunohistochemistry in pure epithelioid PEComa, compared with conventional angiomyolipoma. They also documented the presence of TP53 mutations in some cases of pure epithelioid PEComa, but not in angiomyolipomas.…”