title: TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers.
abstract: Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners; however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization using custom bacterial artificial chromosome probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates subnuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar subnuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3, and ASPL-TFE3 gene fusions, the RCCs are almost always PAX8 positive, cathepsin K negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8 negative, cathepsin K positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCCs are the only known Xp11 translocation RCC molecular subtype that are consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions and should allow for more meaningful clinicopathologic associations to be drawn.
authors.affiliation: Departments of *Pathology †Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD ‡Department of Pathology, New York Medical College, Valhalla §Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Minghao
authors.initials: M
authors.lastname: Zhong
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: John T
authors.initials: JT
authors.lastname: Fallon
authors.forename: Jonathan I
authors.initials: JI
authors.lastname: Epstein
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000293:Adolescent; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D022202:Chromosomes, Artificial, Bacterial; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D054973:Perivascular Epithelioid Cell Neoplasms / Q000235:genetics*; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015514:Oncogene Proteins, Fusion; C069203:TFE3 protein, human