title: Molecular cytogenetic analysis for TFE3 rearrangement in Xp11.2 renal cell carcinoma and alveolar soft part sarcoma: validation and clinical experience with 75 cases.
abstract: Renal cell carcinoma with TFE3 rearrangement at Xp11.2 is a distinct subtype manifesting an indolent clinical course in children, with recent reports suggesting a more aggressive entity in adults. This subtype is morphologically heterogeneous and can be misclassified as clear cell or papillary renal cell carcinoma. TFE3 is also rearranged in alveolar soft part sarcoma. To aid in diagnosis, a break-apart strategy fluorescence in situ hybridization (FISH) probe set specific for TFE3 rearrangement and a reflex dual-color, single-fusion strategy probe set involving the most common TFE3 partner gene, ASPSCR1, were validated on formalin-fixed, paraffin-embedded tissues from nine alveolar soft part sarcoma, two suspected Xp11.2 renal cell carcinoma, and nine tumors in the differential diagnosis. The impact of tissue cut artifact was reduced through inclusion of a chromosome X centromere control probe. Analysis of the UOK-109 renal carcinoma cell line confirmed the break-apart TFE3 probe set can distinguish the subtle TFE3/NONO fusion-associated inversion of chromosome X. Subsequent extensive clinical experience was gained through analysis of 75 cases with an indication of Xp11.2 renal cell carcinoma (n=54), alveolar soft part sarcoma (n=13), perivascular epithelioid cell neoplasms (n=2), chordoma (n=1), or unspecified (n=5). We observed balanced and unbalanced chromosome X;17 translocations in both Xp11.2 renal cell carcinoma and alveolar soft part sarcoma, supporting a preference but not a necessity for the translocation to be balanced in the carcinoma and unbalanced in the sarcoma. We further demonstrate the unbalanced separation is atypical, with TFE3/ASPSCR1 fusion and loss of the derivative X chromosome but also an unanticipated normal X chromosome gain in both males and females. Other diverse sex chromosome copy number combinations were observed. Our TFE3 FISH assay is a useful adjunct to morphologic analysis of such challenging cases and will be applicable to assess the growing spectrum of TFE3-rearranged tumors.
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jennelle C
authors.initials: JC
authors.lastname: Hodge
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Pearce
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Wiktor
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andre M
authors.initials: AM
authors.lastname: Oliveira
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Patricia T
authors.initials: PT
authors.lastname: Greipp
mesh_terms: D000328:Adult; D000368:Aged; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X; D003937:Diagnosis, Differential; D005260:Female; D050939:Gene Fusion; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins; D007621:Karyotyping; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011237:Predictive Value of Tests; D011379:Prognosis; D012042:Registries; D018234:Sarcoma, Alveolar Soft Part / Q000235:genetics* / Q000473:pathology; D014178:Translocation, Genetic; D055815:Young Adult
chemical_list: C422743:ASPSCR1 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; C069203:TFE3 protein, human