TRIM63 Overexpression in FISH-Negative MiTF Family Altered Renal Cell Carcinoma (MiTF RCC)

Area of Science:

• Oncology
• Molecular Pathology
• Genetics

Background:

• MiTF family altered renal cell carcinoma (RCC) diagnosis relies on TFE3/TFEB break-apart FISH assays.
• FISH assays can produce equivocal or false-negative results, particularly with cryptic fusions from intrachromosomal inversions.
• Morphologically suspicious cases with negative FISH require alternative diagnostic methods.

Purpose of the Study:

• To investigate the utility of tripartite motif containing 63 (TRIM63) RNA in situ hybridization (ISH) for diagnosing MiTF RCC.
• To assess if TRIM63 positivity can identify MiTF RCC cases with negative FISH results.
• To correlate TRIM63 expression with MiTF gene rearrangements confirmed by next-generation sequencing (NGS).

Main Methods:

• Retrospective analysis of 20 RCC cases with morphological suspicion for MiTF RCC.
• Cases were TRIM63 positive by RNA ISH and showed negative/equivocal FISH results for TFE3/TFEB rearrangements.
• Next-generation sequencing (NGS) was performed for genomic correlation.

Main Results:

• 14 out of 20 (70%) FISH-negative, TRIM63-positive tumors harbored a MiTF gene rearrangement upon NGS.
• TFE3 rearrangements were identified in 60% (12/20) and TFEB alterations in 10% (2/20) of cases.
• RBM10::TFE3 fusion was present in 67% (8/12) of TFE3 rearranged RCC cases.

Conclusions:

• TRIM63 RNA ISH is a valuable tool for identifying MiTF RCC cases with false-negative or equivocal FISH results.
• This approach is particularly useful for cryptic fusions involving TFE3 or TFEB, including those from Xp11 inversions.
• Combining TRIM63 RNA ISH with FISH and NGS enhances diagnostic accuracy for MiTF RCC.