Proteogenomic characterization of MiT family translocation renal cell carcinoma

Qu, Yuanyuan; Wu, Xiaohui; Anwaier, Aihetaimujiang; Feng, Jinwen; Xu, Wenhao; Pei, Xiaoru; Zhu, Yu; Liu, Yang; Bai, Lin; Yang, Guang; Tian, Xi; Su, Jiaqi; Shi, Guohai; Cao, Dalong; Xu, Fujiang; Wang, Yue; Gan, Hualei; Ni, Shujuan; Sun, Menghong; Zhao, Jian; Zhang, Hailiang; Ye, Dingwei; Chen, Ding

doi:10.1038/s41467-022-34460-w

Cited by 20 publications

(7 citation statements)

References 104 publications

(123 reference statements)

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“…One possibility is that the development of TRCC in Asian populations might be related to exposure to aristolochic acid, a type of carcinogen from traditional Chinese herbs, as recently demonstrated in a large study analyzing the mutational signature of Asian patients with TRCC. 20 Another possibility is related to differences in the biological underpinnings of RCC in African versus European populations, as was recently demonstrated. 7 We acknowledge several limitations in our study.…”

Section: Discussionmentioning

confidence: 97%

Racial Disparities in MiT Family Translocation Renal Cell Carcinoma

Sedehi

et al. 2023

The Oncologist

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Racial disparities have been documented in the biology and outcome of certain renal cell carcinomas (RCCs) among Black patients. However, little is known about racial differences in MiT family translocation RCC (TRCC). To investigate this issue, we performed a case-control study using data from The Cancer Genome Atlas (TCGA) and the Chinese OrigiMed2020 cohort. A total of 676 patients with RCC (14 Asian, 113 Black, and 525 White) were identified in TCGA, and TRCC was defined as RCC with TFE3/TFEB translocation or TFEB amplification, leading to 21 patients with TRCC (2 Asian, 8 Black, 10 White, and 1 unknown). Asian (2 of 14 [14.3%] vs 10 of 525 [1.9%]; P = .036) and Black (8 of 113 [7.1%] vs 1.9%; P = .007) patients with RCC showed significantly higher prevalence of TRCC compared with White patients with RCC. The overall mortality rate of TRCC was slightly higher in Asian and Black patients compared with White patients (HR: 6.05, P = .069). OrigiMed2020 Chinese patients with RCC had a significantly higher proportion of TRCC with TFE3 fusions than TCGA White patients with RCC (13 of 250 [5.2%] vs 7 of 525 [1.3%]; P = .003). Black patients with TRCC were more likely to exhibit the proliferative subtype than White patients (6 of 8 [75%] vs 2 of 9 [22.2%]; P = .057) for those who had RNA-seq profiles. We present evidence of higher prevalence of TRCC in Asian and Black patients with RCC compared with White patients and show that these tumors in Asian and Black patients have distinct transcriptional signatures and are associated with poor outcomes.

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Section: Discussionmentioning

confidence: 97%

Racial Disparities in MiT Family Translocation Renal Cell Carcinoma

Sedehi

et al. 2023

The Oncologist

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“…Recently, a high-throughput sequencing-based study of 79 cases of TFE3 rRCCs indicated that the TCA cycle and respiratory chain were down-regulated in TFE3 rRCC compared to adjacent tissues, which is compliant with Warburg Effect [ 39 ]. However, it is demonstrated in our previous research that mitochondrial respiration is significantly enhanced in TFE3 rRCC than that in ccRCC [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner

Chen,

Lu,

Yang

et al. 2023

J Exp Clin Cancer Res

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Background NONO-TFE3 rearranged renal cell carcinoma (NONO-TFE3 rRCC) is one of a subtype of TFE3 rRCCs with high malignancy and poor prognosis. Compared with clear cell RCC, NONO-TFE3 rRCC shows a preference for mitochondrial respiration. We recently identified that the upregulation of nicotinamide ribokinase 2 (NMRK2) was associated with enhanced mitochondrial respiration and tumor progression in TFE3 rRCC. Methods A tumor-bearing mouse model was established to verify the pro-oncogenic effect of NMRK2 on NONO-TFE3 rRCC. Then the expression of NMRK2 RNA and protein was detected in cell lines and patient specimens. The NMRK2 transcripts were Sanger-sequenced and blasted at NCBI website. We constructed dCas13b-HA system to investigate the factors binding with NMRK2 RNA. We also used molecular experiments like RIP-seq, IP-MS, FISH and fluorescence techniques to explore the mechanisms that long non-coding RNA (lncRNA) like NMRK2 mRNA promoted the mitochondrial respiration of NONO-TFE3 rRCC. The efficacy of the combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was assessed by CCK-8 assay. Results In this study, we confirmed that NMRK2 showed transcriptional-translational conflict and functioned as lncRNA like mRNA in the NONO-TFE3 rRCC. Furthermore, we revealed the molecular mechanism that NONO-TFE3 fusion suppressed the translation of NMRK2 mRNA. Most importantly, three major pathways were shown to explain the facilitation effects of lncRNA like NMRK2 mRNA on the mitochondrial respiration of NONO-TFE3 rRCC in an NAD+ kinase-independent manner. Finally, the efficacy of combination of shRNA (NMRK2)-lentivirus and metformin on NONO-TFE3 rRCC was demonstrated to be superior than either agent alone. Conclusions Overall, our data comprehensively demonstrated the mechanisms for the enhanced mitochondrial respiration in NONO-TFE3 rRCC and proposed lncRNA like NMRK2 mRNA as a therapy target for NONO-TFE3 rRCC. Graphical Abstract

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“…MITF family translocation RCC (t-RCC) is a rare subtype that accounts for 1% to 4% of RCC cases in adults and around 50% in children. 6 It is usually characterized by gene fusions involving transcription factor binding to IGHM enhancer 3 ( TFE3 ) and transcription factor EB ( TFEB ), 2 members of the MITF family of transcription factors. 7 The most common chromosomal translocations associated with tRCC are Xp11, which involves the oncogenic activation of the TFE3 transcription factor, and, less frequently, 6;11 (p21;q12), involving TFEB .…”

Section: Discussionmentioning

confidence: 99%

Incidental Detection of TFEB-Amplified Renal Cell Carcinoma by Colocated Gene Amplification of CCND3 (6p21): A Case Report and Review of the Literature

et al. 2023

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TFEB-amplified renal cell carcinoma (RCC), which belongs to the MITF family of RCC, is characterized by genomic amplification at the 6p21.1 locus where the TFEB gene is located. The vascular endothelial growth factor A and cyclin D3 genes are also located at this same locus. When tumors lack classic morphologic features, they may be classified as “RCC not otherwise specified (NOS).” However, it is increasingly important to accurately diagnose the RCC subtype to define the patient's individual prognosis and select the subsequent therapeutic modalities, which now include targeted agents. Therefore, knowledge of the diagnostic features of TFEB-altered RCCs, such as t(6;11) RCCs and TFEB-amplified RCCs, is critical for identifying these tumors. Herein, we present an interesting case of TFEB-amplified RCC that was initially diagnosed as RCC NOS on biopsy of a renal tumor in a community practice setting with available molecular findings demonstrating CCND3 amplification. The genetic abnormality was “accidentally” detected due to the amplification of the colocated CCND3 gene at the 6p21 locus of the TFEB gene on a limited genetic sequencing panel. This case highlights the importance of molecular tests in accurately diagnosing RCC and carefully interpreting molecular findings in the context of histomorphologic features.

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Proteogenomic characterization of MiT family translocation renal cell carcinoma

Cited by 20 publications

References 104 publications

Racial Disparities in MiT Family Translocation Renal Cell Carcinoma

Racial Disparities in MiT Family Translocation Renal Cell Carcinoma

LncRNA like NMRK2 mRNA functions as a key molecular scaffold to enhance mitochondrial respiration of NONO-TFE3 rearranged renal cell carcinoma in an NAD+ kinase-independent manner

Incidental Detection of TFEB-Amplified Renal Cell Carcinoma by Colocated Gene Amplification of CCND3 (6p21): A Case Report and Review of the Literature

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