RBM10-TFE3 Renal Cell Carcinoma

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 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 immunohistochemistry. Prompted by a case report in the cytogenetics literature, we identify three 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 immunohistochemistry and TFE3 FISH.

The suitability of NONO-TFE3 dual-fusion FISH assay as a diagnostic tool for NONO-TFE3 renal cell carcinoma

“…Nowadays, ASPSCR1, PRCC , and SFPQ are recognized as relatively common gene fusion partners associated with Xp11.2 translocation renal cell carcinoma 8,19 . However, the involvement of NONO, CLTC, LUC7L3, and RBM10 have only been discussed in case reports 8,[20][21][22] . FISH is currently the most convenient and effective method for identifying gene alteration by using custom BAC probes on FFPE tissue sections.…”

Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

“…Break-apart FISH for TFE3 or TFEB avoids issues related to PCR amplification and is easier to conduct than RT-PCR. However, false-negative results using common break-apart FISH probes in Xp11 tRCC with an RBM10-TFE3 or NONO-TFE3 fusion were reported [ 48 , 49 ]. RBM10 is located at Xp11.23, only 1.8 Mb from TFE3 .…”

“…NONO is located at Xq13.1, also near TFE3 . Therefore, performing FISH with specific probes for RBM10-TFE3 and NONO-TFE3 fusions may be necessary [ 48 , 49 ].…”

PRCC-TFE3 dual-fusion FISH assay: A new method for identifying PRCC-TFE3 renal cell carcinoma in paraffin-embedded tissue

“…Most common gene fusions in Xp11.2 tRCC are TFE3 gene on Xp11.2 with PRCC at 1q21 and TFE3 with ASPL at 17q25, which arise from the translocations t(X; 1) (p11.2; q21)[ 5 ] and t(X; 17) (p11.2; q25.3)[ 6 ]. Other less recurrent reported TFE3 fusion partners include SFPQ (alias PSF ), NonO [ 7 ], CLTC [ 8 ] and RBM10 [ 9 ], resulting from t(X; 1) (p11.2; p34), inv(X) (p11.2q12), t(X; 17) (p11.2; q23), and inv(X) (p11.2p11.23), respectively. Some fusion partners, such as PARP14 [ 10 ], KHTFESRP [ 11 ], LUC7L3 [ 11 ] and DVL2 [ 12 ], have only been identified in single patients.…”

“…Among Xp11.2 RCCs, approximately 60% label for cathepsin K, while almost all conventional RCCs stain negative [ 20 , 22 ]. Recently, break-apart fluorescence in situ hybridization (FISH) assay in FFPE archival sections is viewed as the optimal test for diagnosing Xp11.2 RCC for most laboratories [ 23 ] (However, the break-apart FISH assay is less useful than TFE3 immunohistochemistry in detecting some Xp11.2 RCCs, like the RBM10-TFE3 RCC which are associated with a subtle chromosome inversion [ 9 ]. ), while it is unable to identify the fusion partner of TFE3 gene.…”