MiT/TFE Family Renal Cell Carcinoma

Abstract

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. The germline variant of MITF p.E318K has been reported as a risk factor for RCC. E 318 is present at the SUMOylation consensus site of MITF. The p.E318K variant abrogates SUMOylation on K 316, which results in alteration of MITF transcriptional activity. Only a few cases of MITF p.E318K RCC have been reported, and their clinical features have not yet been fully described. It would be important for clinicians to recognize MITF p.E318K RCC and consider MITF germline testing for undiagnosed familial RCC cases. This review outlines the involvement of the MiT/TFE transcription factors in RCC, both in sporadic and hereditary cases. Further elucidation of the molecular function of the MiT/TFE family is necessary for better diagnosis and treatment of these rare diseases.

Keywords: MITF; MiT/TFE family; RCC; SUMO; TFE3; TFEB.

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.

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.

Figure 3

Hypothetical model of MITF p.E318K RCC development. The MITF p.E318K germline variant is a mild susceptibility allele. In addition to the germline variant, somatic alterations such as chromosome 7 and 17 amplification, unknown gene mutations, or epigenetic alteration might be required for MITF p.E318K RCC development.