PMID- 33854184 OWN - NLM STAT- MEDLINE DCOM- 20220124 LR - 20230210 IS - 1530-0285 (Electronic) IS - 0893-3952 (Print) IS - 0893-3952 (Linking) VI - 34 IP - 8 DP - 2021 Aug TI - TRIM63 is a sensitive and specific biomarker for MiT family aberration-associated renal cell carcinoma. PG - 1596-1607 LID - 10.1038/s41379-021-00803-z [doi] AB - 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. CI - (c) 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology. FAU - Wang, Xiao-Ming AU - Wang XM AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Zhang, Yuping AU - Zhang Y AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Mannan, Rahul AU - Mannan R AUID- ORCID: 0000-0002-6642-0468 AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Skala, Stephanie L AU - Skala SL AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA. FAU - Rangaswamy, Roshni AU - Rangaswamy R AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Chinnaiyan, Anya AU - Chinnaiyan A AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Su, Fengyun AU - Su F AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Cao, Xuhong AU - Cao X AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Zelenka-Wang, Sylvia AU - Zelenka-Wang S AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - McMurry, Lisa AU - McMurry L AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Xiao, Hong AU - Xiao H AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Spratt, Daniel E AU - Spratt DE AD - Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Sangoi, Ankur R AU - Sangoi AR AD - Department of Pathology, El Camino Hospital, Mountain View, CA, USA. FAU - Shao, Lina AU - Shao L AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Betz, Bryan L AU - Betz BL AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Brown, Noah AU - Brown N AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. FAU - Tickoo, Satish K AU - Tickoo SK AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - McKenney, Jesse K AU - McKenney JK AD - Robert J Tomsich Pathology and Laboratory Medicine Institute, Anatomic Pathology, Cleveland Clinic, Cleveland, OH, USA. FAU - Argani, Pedram AU - Argani P AD - Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. FAU - Gupta, Sounak AU - Gupta S AD - Mayo Clinic, Rochester, MN, USA. FAU - Reuter, Victor E AU - Reuter VE AD - Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. FAU - Chinnaiyan, Arul M AU - Chinnaiyan AM AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. AD - Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA. AD - Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Howard Hughes Medical Institute, Ann Arbor, MI, USA. FAU - Dhanasekaran, Saravana M AU - Dhanasekaran SM AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. FAU - Mehra, Rohit AU - Mehra R AUID- ORCID: 0000-0002-6955-8884 AD - Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA. mrohit@med.umich.edu. AD - Michigan Center for Translational Pathology, Ann Arbor, MI, USA. mrohit@med.umich.edu. AD - Rogel Cancer Center, Michigan Medicine, Ann Arbor, MI, USA. mrohit@med.umich.edu. LA - eng GR - P30 CA008748/CA/NCI NIH HHS/United States GR - P30 CA046592/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210414 PL - United States TA - Mod Pathol JT - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JID - 8806605 RN - 0 (Basic Helix-Loop-Helix Leucine Zipper Transcription Factors) RN - 0 (Biomarkers, Tumor) RN - 0 (MITF protein, human) RN - 0 (Microphthalmia-Associated Transcription Factor) RN - 0 (Muscle Proteins) RN - 0 (TFE3 protein, human) RN - 0 (TFEB protein, human) RN - 0 (Tripartite Motif Proteins) RN - EC 2.3.2.27 (TRIM63 protein, human) RN - EC 2.3.2.27 (Ubiquitin-Protein Ligases) RN - Familial renal cell carcinoma SB - IM MH - Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics MH - Biomarkers, Tumor/*analysis MH - Carcinoma, Renal Cell/*diagnosis/genetics/pathology MH - Humans MH - Kidney Neoplasms/*diagnosis/genetics/pathology MH - Microphthalmia-Associated Transcription Factor/genetics MH - Muscle Proteins/analysis/*metabolism MH - Oncogene Fusion MH - Sensitivity and Specificity MH - Translocation, Genetic MH - Tripartite Motif Proteins/analysis/*metabolism MH - Ubiquitin-Protein Ligases/analysis/*metabolism PMC - PMC8298271 MID - NIHMS1692185 COIS- Conflict of interest The authors declare no conflict of interest. EDAT- 2021/04/16 06:00 MHDA- 2022/01/27 06:00 PMCR- 2022/02/01 CRDT- 2021/04/15 07:08 PHST- 2020/11/19 00:00 [received] PHST- 2021/03/20 00:00 [accepted] PHST- 2021/03/19 00:00 [revised] PHST- 2021/04/16 06:00 [pubmed] PHST- 2022/01/27 06:00 [medline] PHST- 2021/04/15 07:08 [entrez] PHST- 2022/02/01 00:00 [pmc-release] AID - S0893-3952(22)00573-7 [pii] AID - 10.1038/s41379-021-00803-z [doi] PST - ppublish SO - Mod Pathol. 2021 Aug;34(8):1596-1607. doi: 10.1038/s41379-021-00803-z. Epub 2021 Apr 14.