MiTF/TFE Translocation Renal Cell Carcinomas: From Clinical Entities to Molecular Insights

Abstract

MiTF/TFE translocation renal cell carcinoma (tRCC) is a rare and aggressive subtype of RCC representing the most prevalent RCC in the pediatric population (up to 40%) and making up 4% of all RCCs in adults. It is characterized by translocations involving either TFE3 (TFE3-tRCC), TFEB (TFEB-tRCC) or MITF, all members of the MIT family (microphthalmia-associated transcriptional factor). TFE3-tRCC was first recognized in the World Health Organization (WHO) classification of kidney cancers in 2004. In contrast to TFEB-tRCC, TFE3-tRCC is associated with many partners that can be detected by RNA or exome sequencing. Both diagnoses of TFE3 and TFEB-tRCC are performed on morphological and immunohistochemical features, but, to date, TFE break-apart fluorescent in situ hybridization (FISH) remains the gold standard for diagnosis. The clinical behavior of tRCC is heterogeneous and more aggressive in adults. Management of metastatic tRCC is challenging, especially in the younger population, and data are scarce. Efficacy of the standard of care-targeted therapies and immune checkpoint inhibitors remains low. Recent integrative exome and RNA sequencing analyses have provided a better understanding of the biological heterogeneity, which can contribute to a better therapeutic approach. We describe the clinico-pathological entities, the response to systemic therapy and the molecular features and techniques used to diagnose tRCC.

TFEB‐translocated and ‐amplified renal cell carcinoma with VEGFA co‐amplification: A case of long‐term control by multimodal therapy including a vascular endothelial growth factor‐receptor inhibitor

“… 3 Most cases of TFEB translocation RCC reportedly have an indolent clinical course. 4 The TFEB is located in the short arm of chromosome 6, specifically in the 6p21‐p23 region. 5 The most commonly reported fusion partner for the TFEB is the MALAT1 (81%), 4 and more recent studies have revealed ACTB , NEAT1 , 6 COL21A1 , and CADM2 7 as rarer fusion partners.…”

“… 4 The TFEB is located in the short arm of chromosome 6, specifically in the 6p21‐p23 region. 5 The most commonly reported fusion partner for the TFEB is the MALAT1 (81%), 4 and more recent studies have revealed ACTB , NEAT1 , 6 COL21A1 , and CADM2 7 as rarer fusion partners. In the present case, the fusion partner and the exact fusion point could have been identified by reverse‐transcription polymerase chain reaction.…”

“…There is no remarkable sex predominance (female:male ratio, 0.75:1.00) 3 . Most cases of TFEB translocation RCC reportedly have an indolent clinical course 4 . The TFEB is located in the short arm of chromosome 6, specifically in the 6p21‐p23 region 5 .…”

Multicystic Clear Cell Renal Tumors With Low-grade Nuclear Features: Time to Include TFE3 Translocation-associated Carcinomas

“…2,3 Although older age and advanced stage have been shown to independently predict poor outcome in these tumors, 4 biological behavior and clinical prognosis may also partially depend on the TFE3 gene fusion partner. 5,6 For example, patients with ASPSCR1::TFE3 fusion associated RCC have significantly shorter overall survival compared with patients with non-ASPSCR1::TFE3 fusion associated RCC. 4,7 TFE3-rearranged RCC is driven by constitutively active chimeric TFE3 fusion proteins, which universally retain the C-terminal bHLH/LZ dimerization/DNA-binding domain and putative nuclear localization signal of TFE3.…”

“…Most are biologically aggressive with similar cancer specific survival compared with clear cell renal cell carcinoma (ccRCC) 2,3 . Although older age and advanced stage have been shown to independently predict poor outcome in these tumors, 4 biological behavior and clinical prognosis may also partially depend on the TFE3 gene fusion partner 5,6 . For example, patients with ASPSCR1 :: TFE3 fusion associated RCC have significantly shorter overall survival compared with patients with non- ASPSCR1 :: TFE3 fusion associated RCC 4,7 …”