RBM10‐TFE3 fusions: A FISH‐concealed anomaly in adult renal cell carcinomas displaying a variety of morphological and genomic features: Comprehensive study of six novel cases

Abstract

The accurate diagnosis of Xp11‐translocation renal cell carcinoma (RCC) in adults is challenging. TFE3 (located on chromosome X) fuses with a partner gene generally located on another chromosome. In rare cases TFE3 may fuse with a neighboring gene: RBM10. Because TFE3 false‐positive immunostaining is a common pitfall in many laboratories, demonstration of the chromosomal rearrangement is required in order to ascertain the diagnosis. Fluorescence in situ hybridization (FISH)—that has been considered as the gold standard method—reaches its limits for detecting small Xp11 paracentric inversions. We performed a comprehensive clinical, histological and genomic study of six novel cases of RCC with RBM10‐TFE3 fusion. Using FISH, TFE3 rearrangement was equivocal in one case and negative in others. RBM10‐TFE3 fusion was discovered using targeted RNA sequencing (RNASeq). As all the previously reported cases (mean age: 50), the six patients were adults (mean age: 42), suggesting an epidemiologic difference between RBM10‐TFE3 RCC and tumors harboring some other partner genes, such as ASPSCR1 that rather occur in children. Array‐comparative genomic hybridization showed several alterations, notably a gain of 17q in four cases with papillary features and loss of 3p in one case with clear cells. Our study demonstrates that, though rare among adult cases of RCC, RBM10‐TFE3 fusion is not exceptional and warrants appropriate molecular detection. Notably, it would be worthy to systemically investigate by RNASeq challenging RCC with type‐2 papillary features and 17q gain.

MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights

“…Typical break-apart signals of TFE3 gene translocation consist and green signals, the normal result being a merged hybridization signal, a FISH assays may show equivocal or false-negative results due to intrachrom versions involving TFE3, resulting in a subtly spaced fluorescence signal that ous to visualize than a translocation. This difficulty has been demonstrated fo ments involving NONO, GRIPAP1, RBMX and RBM10, consisting of the pe paracentric inversion of chromosome X, respectively, for which there is close p the genes involved in the rearrangement [27,28]. In the case of a strong suspic with negative FISH, specific targeted RT-PCR or RNA sequencing (RNA-seq exome sequencing is recommended.…”

Chameleon TFE3-translocation RCC and How Gene Partners Can Change Morphology: Accurate Diagnosis Using Contemporary Modalities

“…The list of TFE3 fusion partners is growing rapidly, especially since the widespread utilization of RNA-sequencing, and based on our comprehensive literature review of tissue-based studies encountered 22 genes 5–7,12,13,22,26,30,35–44. Two thirds of TFE3-tRCC cases with a known fusion partner and 50% of novel fusion subtypes were published within the last 5 years, and the total number of reported adult tumors with available clinicopathologic features reached 397 cases (cut-off December 1, 2021).…”

“…False negative results using conventional break-apart FISH assay is a known pitfall, since RBM10-TFE3 cryptic fusion represents a 1.8 mb paracentric Xp11 inversion with subtle split signals 57,58. Hence, the majority of reported cases were definitively classified using custom designed fosmid FISH probes, reverse transcription polymerase chain reaction or RNA-seq 32,36,38,39,57,58. Patients’ outcomes are variable with indolent disease in >75% cases, but recurrences and metastases in the remaining cases 26,38.…”

“…RNA-seq is effective in simultaneous detecting of multiple gene rearrangements (without prior knowledge of the fusion partners), single nucleotide variants, insertions, deletions, and copy number changes 13,84,85. The highly customizable targeted RNA-seq technology was adopted and validated on hundreds of renal tumors producing invaluable information of novel fusion partner genes, their frequency, detailed analysis of fusion structures, mapping of breakpoints, exons and functional domains, consequently facilitating clinicopathologic associations and explaining heterogeneity of TFE3-tRCC subtypes 13,22,26,29,32,35,37–40,43,44,47,54,57,60. RNA-seq could be utilized to verify FISH results or to replace FISH in view of substantial advantages and despite some drawbacks related to RNA degradation in old or decalcified tissues, high cost and technical complexity (Table 3).…”

“…The list of TFE3 fusion partners is growing rapidly, especially since the widespread utilization of RNAsequencing, and based on our comprehensive literature review of tissue-based studies encountered 22 genes. [5][6][7]12,13,22,26,30,[35][36][37][38][39][40][41][42][43][44] Two thirds of TFE3-tRCC cases with a known fusion partner and 50% of novel fusion subtypes were published within the last 5 years, and the total number of reported adult tumors with available clinicopathologic features reached 397 cases (cut-off December 1, 2021). The list of TFE3 partner genes presented in descending order of their frequency includes ASPSCR1, PRCC, SFPQ, NONO, RBM10, MED15, LUC7L3, FUBP1, DVL2, EWSR1, SETD1B, ZC3H4, ARID1B, CLTC, GRIPAP1, KAT6A, KHSRP, MATR3, NEAT1, PARP14, TMED6, and U2AF2 (Table 1).…”