TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma

• Published in: Modern pathology 2021-08, Vol.34 (8), p.1596-1607
• Main Authors: Wang, Xiao-Ming, Zhang, Yuping, Mannan, Rahul, Skala, Stephanie L., Rangaswamy, Roshni, Chinnaiyan, Anya, Su, Fengyun, Cao, Xuhong, Zelenka-Wang, Sylvia, McMurry, Lisa, Xiao, Hong, Spratt, Daniel E., Sangoi, Ankur R., Shao, Lina, Betz, Bryan L., Brown, Noah, Tickoo, Satish K., McKenney, Jesse K., Argani, Pedram, Gupta, Sounak, Reuter, Victor E., Chinnaiyan, Arul M., Dhanasekaran, Saravana M., Mehra, Rohit
• Format: Article
• Language: English
• Subjects: 14/32; 38/71; 38/91; 631/67/1857; 692/308/53/2421; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Biomarkers; Biomarkers, Tumor - analysis; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - pathology; Chromosome rearrangements; Diagnosis; Fluorescence in situ hybridization; Humans; Kidney cancer; Kidney Neoplasms - diagnosis; Kidney Neoplasms - genetics; Kidney Neoplasms - pathology; Laboratory Medicine; Medicine; Medicine & Public Health; Microphthalmia-associated transcription factor; Microphthalmia-Associated Transcription Factor - genetics; Muscle Proteins - analysis; Muscle Proteins - metabolism; Oncogene Fusion; Pathology; Renal cell carcinoma; Sensitivity and Specificity; Translocation, Genetic; Tripartite Motif Proteins - analysis; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - analysis; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/s41379-021-00803-z

Microphthalmia-associated transcription factor (MiT) family aberration-associated renal cell carcinoma (MiTF-RCC) is a subtype of renal cell carcinoma harboring recurrent chromosomal rearrangements involving TFE3 or TFEB genes. MiTF-RCC is morphologically diverse, can histologically resemble common RCC subtypes like clear cell RCC and papillary RCC, and often poses a diagnostic challenge in genitourinary clinical and pathology practice. To characterize the MiTF-RCC at the molecular level and identify biomarker signatures associated with MiTF-RCC, we analyzed RNAseq data from MiTF-RCC, other RCC subtypes and benign kidney. Upon identifying TRIM63 as a cancer-specific biomarker in MiTF-RCC, we evaluated its expression independently by RNA in situ hybridization (RNA-ISH) in whole tissue sections from 177 RCC cases. We specifically included 31 cytogenetically confirmed MiTF-RCC cases and 70 RCC cases suspicious for MiTF-RCC in terms of clinical and morphological features, to evaluate and compare TRIM63 RNA-ISH results with the results from TFE3/TFEB fluorescence in situ hybridization (FISH), which is the current clinical standard. We confirmed that TRIM63 mRNA was highly expressed in all classes of MiTF-RCC compared to other renal tumor categories, where it was mostly absent to low. While the TRIM63 RNA-ISH and TFE3/TFEB FISH results were largely concordant, importantly, TRIM63 RNA-ISH was strongly positive in TFE3 FISH false-negative cases with RBM10-TFE3 inversion. In conclusion, TRIM63 can serve as a diagnostic marker to distinguish MiTF-RCC from other renal tumor subtypes with overlapping morphology. We suggest a combination of TFE3/TFEB FISH and TRIM63 RNA-ISH assays to improve the accuracy and efficiency of MiTF-RCC diagnosis. Accurate diagnosis of MiTF-RCC and other RCC subtypes would enable effective targeted therapy and avoid poor therapeutic response due to tumor misclassification.