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Tang, J.;  Baba, M. Microphthalmia Family Translocation Renal Cell Carcinoma. Encyclopedia. Available online: https://encyclopedia.pub/entry/40199 (accessed on 25 December 2025).
Tang J,  Baba M. Microphthalmia Family Translocation Renal Cell Carcinoma. Encyclopedia. Available at: https://encyclopedia.pub/entry/40199. Accessed December 25, 2025.
Tang, Jinglong, Masaya Baba. "Microphthalmia Family Translocation Renal Cell Carcinoma" Encyclopedia, https://encyclopedia.pub/entry/40199 (accessed December 25, 2025).
Tang, J., & Baba, M. (2023, January 16). Microphthalmia Family Translocation Renal Cell Carcinoma. In Encyclopedia. https://encyclopedia.pub/entry/40199
Tang, Jinglong and Masaya Baba. "Microphthalmia Family Translocation Renal Cell Carcinoma." Encyclopedia. Web. 16 January, 2023.
Microphthalmia Family Translocation Renal Cell Carcinoma
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This entry is adapted from the peer-reviewed paper 10.3390/genes14010151

The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family of transcription factors are evolutionarily conserved, basic helix–loop–helix leucine zipper (bHLH-Zip) transcription factors, consisting of MITF, TFEB, TFE3, and TFEC. MiT/TFE proteins, with the exception of TFEC, are involved in the development of renal cell carcinoma (RCC). Most of the MiT/TFE transcription factor alterations seen in sporadic RCC cases of MiT family translocation renal cell carcinoma (tRCC) are chimeric proteins generated by chromosomal rearrangements. These chimeric MiT/TFE proteins retain the bHLH-Zip structures and act as oncogenic transcription factors. 

MiT/TFE family RCC MITF

1. The Microphthalmia/Transcription Factor E (MiT/TFE) Family

The microphthalmia-associated transcription factor/transcription factor E (MiT/TFE) family consists of MITF, TFEB, TFE3, and TFEC. All of the proteins have a bHLH-Zip (basic helix–loop–helix leucine zipper) structure, which allows them to form homodimers or heterodimers with each other and bind to the regulatory elements of target genes [1][2][3][4]. The binding consensus sequences recognized by the MiT/TFE proteins are known as the E-box motif (CACGTG) and M-box motif (TCATGTG) [5][6][7][8]. The MiT/TFE proteins are the master regulators of lysosomal biogenesis and autophagy [9]. In addition, their fundamental roles in many cellular processes including proliferation, differentiation, survival, senescence, invasion, metabolism, organelle biogenesis, and stress responses are emerging [1][2][3]. Both MiT family translocation renal cell carcinoma (tRCC) and MITF p.E318K renal cell carcinoma (RCC) are rare and not widely recognized by clinicians. In the future, it will be necessary to increase awareness of these MiT/TFE family RCCs and develop biomarkers to facilitate diagnosis.

2. MiT Family Translocation Renal Cell Carcinoma (tRCC)

MiT family translocation renal cell carcinoma (tRCC) is a sporadic RCC characterized by fusion genes involving the MiT/TFE family genes, MITF, TFEB, and TFE3 and defined as an MiT family translocation RCC in the 2016 WHO classification [10][11]. In the 2022 WHO classification, tRCC is divided into TFE3-rearranged RCC and TFEB-altered RCC as Moleculary-defined RCCs [12]. tRCC is a rare disease that accounts for approximately 1–5% of sporadic RCC in adults [13][14][15][16][17], developing more often in women than in men, and is much more commonly seen in pediatric RCC cases (approximately 40% (range 20–75%)) [13][18][19][20][21]. tRCC tends to be in an advanced stage at onset with a more aggressive presentation than other sporadic RCCs, and molecular targeted therapy for advanced cases has not yet been established [10][22]. The most distinctive histopathological features of tRCC are clear-cell papillary, displaying a papillary structure consisting of clear cells. However, recent studies have shown that tRCCs are morphologically heterogenous and can include papillary, tubular, acinar, and even cystic architecture [10][17][23][24]. In fact, some cases are indistinguishable from clear-cell (cc)RCC or papillary (p)RCC by H&E staining alone [16]. Therefore, it is expected that the actual number of tRCC cases may be higher than the number currently diagnosed. Definitive diagnosis requires TFE3/TFEB/MITF immunohistochemistry and FISH [25][26][27], which are not routinely performed in many hospitals. Hence, the immunohistochemistry of surrogate markers such as cathepsin K, Melan A, and GPNMB should be considered for the initial diagnosis of RCC [18][24][28]. Chimeric MiT/TFE proteins are generated by chromosomal rearrangements. Bakouny et al. have reported that among 88 fusion-defined tRCC cases, most fusion genes (88.6%) involved TFE3. On the other hand, TFEB fusions were reported in only 9.1% and MITF fusions in only 2.3% of these cases [16]. A single center study of the largest TFE3-rearranged RCC cohort published to date identified 57 TFE3 fusion genes in 4581 RCCs [17]. Of the 57 cases, 26.3% were SFPQ-TFE3 fusions and 22.8% were ASPSCR1-TFE3 fusions. Of note, X chromosomal inversion was noted in 21% (12/57) of cases, which consisted of NONO-TFE3 (14%) and RBM10-TFE3 (7%). These X chromosomal inversion cases can be misdiagnosed as non-TFE3-rearranged RCC because of the narrow interval between split signals seen with TFE3 gene break-apart FISH, the gold standard diagnostic test for TFE3-rearranged RCC [29][30]. (Figure 1a–d) TFEB-altered RCC includes 6p21.1 translocated RCC and 6p21.1 amplified RCC, which demonstrate distinct signals seen with TFEB gene break-apart FISH (Figure 1e,f) [31]. All MiT/TFE fusion genes identified to date retain the bHLH-Zip structure (Figure 2) [16][17][22][32][33][34][35][36], suggesting that these MiT/TFE fusion genes function as oncogenic transcription factors. Indeed, overexpression of TFE3 fusion, PRCC–TFE3, in mouse kidneys was shown to cause RCC with aberrant expression of MiT/TFE target genes [28]. There are few recurrent genomic alterations in tRCC other than MiT/TFE gene rearrangement and 9p21.3 deletion [16]. Several genomic alterations, such as ASPSCR1-TFE3, LUC7L3-TFE3, and 22q deletion, correlate with poor prognosis [17][18]. Currently, there is no established standard therapy for advanced tRCC [10][22]. However, recent studies suggest that immunotherapy may be effective for advanced tRCC [16][17].
Genes 14 00151 g001
Figure 1. A diagram of TFE3 gene break-apart FISH. (a) The TFE3 gene is located at chromosome Xp11.2. The 5′ FISH probe for TFE3 is green. The 3′ FISH probe for TFE3 is red. A fusion candidate gene, RBM10 (blue bar), is located at chromosome Xp11.23 on the telomere side of TFE3. Another fusion candidate gene, NONO (brown bar), is located at chromosome Xq13.1. The TFE3 gene break-apart FISH demonstrates co-localization of the green and red probes. (b) An intra Xp (paracentric) inversion inv(X)(p11.2;p11.23) causes the RBM10–TFE3 fusion gene. The TFE3 gene break-apart FISH demonstrates subtle split red and green signals. Two blue bars indicate separated RBM10. The length of the two-arrowhead line indicates the relative distance between the FISH signals. (c) A pericentric X chromosome inversion, inv(X)(p11.2;q13.1), causes the NONO–TFE3 fusion gene. The TFE3 gene break-apart FISH demonstrates slight split red and green signals. The two brown bars indicate separated NONO. The length of the two-arrowhead line indicates the relative distance between the FISH signals. (d) Xp11.2 translocation may occur with another chromosome. The TFE3 gene break-apart FISH demonstrates clearly separated green and red signals. The length of the two-arrowhead line indicates the relative distance between the FISH signals. (e) The TFEB gene is located at chromosome 6p21.1. The 5′ FISH probe for TFEB is green. The 3′ FISH probe for TFEB is red. 6p21.1 translocated RCC demonstrates clearly separated green and red signals as well as co-localized green and red signals by TFEB gene break-apart FISH. (f) 6p21.1 amplified RCC demonstrates amplification of co-localized green and red signals by TFEB gene break-apart FISH.
Genes 14 00151 g002
Figure 2. Structures of TFE3 fusion and TFEB fusion genes. The structures of TFE3 fusions and TFEB fusions found in TFE3-rearranged RCC and TFEB-altered RCC are shown. Wild-type TFE3 and TFEB have 10 exons. The fusion partner genes are listed. All of the fusion genes retain coding exons for the bHLH-Zip domain. AD: activation domain; bHLH-Zip: basic helix–loop–helix leucine zipper.

References

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Subjects: Genetics & Heredity
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register : Jinglong Tang , Masaya Baba
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Update Date: 16 Jan 2023
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