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

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2021 Aug

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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. © 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.

Citation

Xiao-Ming Wang, Yuping Zhang, Rahul Mannan, Stephanie L Skala, Roshni Rangaswamy, Anya Chinnaiyan, Fengyun Su, Xuhong Cao, Sylvia Zelenka-Wang, Lisa McMurry, Hong Xiao, Daniel E Spratt, Ankur R Sangoi, Lina Shao, Bryan L Betz, Noah Brown, Satish K Tickoo, Jesse K McKenney, Pedram Argani, Sounak Gupta, Victor E Reuter, Arul M Chinnaiyan, Saravana M Dhanasekaran, Rohit Mehra. TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2021 Aug;34(8):1596-1607