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.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2021 Apr 14 [Epub ahead of print]
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
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, Ann Arbor, MI, USA., Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA., Department of Pathology, El Camino Hospital, Mountain View, CA, USA., Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Robert J Tomsich Pathology and Laboratory Medicine Institute, Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA., Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Mayo Clinic, Rochester, MN, USA., Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. .
PubMed http://www.ncbi.nlm.nih.gov/pubmed/33854184