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, paraffinembedded 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 ¼ 54), alveolar soft part sarcoma (n ¼ 13), perivascular epithelioid cell neoplasms (n ¼ 2), chordoma (n ¼ 1), or unspecified (n ¼ 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.

Long non‑coding RNA ZNF674‑1 acts as a cancer suppressor in nasopharyngeal carcinoma

“…A previous study identified that lncRNA ZNF674-1 was aberrantly expressed in primary NPC tissues; however, the function of lncRNA ZNF674-1 in NPC is yet to be investigated (17). lncRNA ZNF674-1 is situated at chromosomal location Xp11, and is 626 bp (17) and it has been identified that Xp11.2 translocation is closely associated with renal cell carcinoma tumorigenesis (34,35). This indicates that lncRNA ZNF674-1 may be a cancer-associated gene involved the carcinogenesis of NPC.…”

Diagnostically Challenging Epithelioid Soft Tissue Tumors

“…Importantly, a subset of pediatric RCCs show a X;17 translocation, which is typically balanced. 46 These RCCs demonstrate papillary architecture, clear to eosinophilic cytoplasm, and psammoma bodies. 47 Fluorescence in situ hybridization (FISH) probes to differentiate balanced versus unbalanced X;17 translocations have been devised, and may be of use in cases of metastatic disease with unknown primary.…”

“…47 Fluorescence in situ hybridization (FISH) probes to differentiate balanced versus unbalanced X;17 translocations have been devised, and may be of use in cases of metastatic disease with unknown primary. 46 Malignant melanomas with epithelioid morphology can have some overlap with ASPS, but can be differentiated by immunoreactivity for melanocytic markers and lack of PAS-D-positive crystals.…”

Molecular diagnosis of soft tissue neoplasia: clinical applications and recent advances

“…TFE3 belongs to the MiTF family of transcription factors, which share a common helix-loop-helix leuzine zipper dimerization motif, a transactivation domain and a basic region involved in DNA contact and binding. TFE3 is a fusion partner for multiple other tumors including Xp11 translocation-associated renal cell carcinomas, alveolar soft-part sarcoma and a subset of PEComas [37][38][39]. In all tumors, the bHLH-LZ and transcriptional activation domain of TFE3 is conserved in the fusion and the ultimate outcome is high-level expression of TFE3.…”