title: RBM10-TFE3 Renal Cell Carcinoma: A Potential Diagnostic Pitfall Due to Cryptic Intrachromosomal Xp11.2 Inversion Resulting in False-negative TFE3 FISH.
abstract: Xp11 translocation renal cell carcinoma (RCC) are defined by chromosome translocations involving the Xp11 breakpoint which results in one of a variety of TFE3 gene fusions. TFE3 break-apart florescence in situ hybridization (FISH) assays are generally preferred to TFE3 immunohistochemistry (IHC) as a means of confirming the diagnosis in archival material, as FISH is less sensitive to the variable fixation which can result in false positive or false negative IHC. Prompted by a case report in the cytogenetics literature, we identify 3 cases of Xp11 translocation RCC characterized by a subtle chromosomal inversion involving the short arm of the X chromosome, resulting in an RBM10-TFE3 gene fusion. TFE3 rearrangement was not detected by conventional TFE3 break-apart FISH, but was suggested by strong diffuse TFE3 immunoreactivity in a clean background. We then developed novel fosmid probes to detect the RBM10-TFE3 gene fusion in archival material. These cases validate RBM10-TFE3 as a recurrent gene fusion in Xp11 translocation RCC, illustrate a source of false-negative TFE3 break-apart FISH, and highlight the complementary role of TFE3 IHC and TFE3 FISH.
authors.affiliation: Departments of *Pathology †Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD ‡Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY.
authors.forename: Pedram
authors.initials: P
authors.lastname: Argani
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Victor E
authors.initials: VE
authors.lastname: Reuter
authors.forename: Satish K
authors.initials: SK
authors.lastname: Tickoo
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D015142:Baltimore; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000032:analysis / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D056657:Cathepsin K / Q000032:analysis; D007446:Chromosome Inversion; D041321:Chromosomes, Human, X; D005188:False Negative Reactions; D005260:Female; D050939:Gene Fusion; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007680:Kidney Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D009519:New York City; D011237:Predictive Value of Tests; D016601:RNA-Binding Proteins / Q000235:genetics*; D015203:Reproducibility of Results
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; C512260:RBM10 protein, human; D016601:RNA-Binding Proteins; C069203:TFE3 protein, human; C534130:CTSK protein, human; D056657:Cathepsin K