TFE3 Rearrangements in Adult Renal Cell Carcinoma

Sukov, William R.; Hodge, Jennelle C.; Lohse, Christine M.; Leibovich, Bradley C.; Thompson, R. Houston; Pearce, Kathryn E.; Wiktor, Anne E.; Cheville, John C.

doi:10.1097/pas.0b013e31824dd972

Cited by 128 publications

(44 citation statements)

References 22 publications

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“…This has also been found in Alpha-TFEB translocation (11). Furthermore, KHDRBS2 contains a KH-type splicing regulatory domain that is involved in RNA splicing, as does KHSRP, and the majority of TFE3 partners.…”

Section: Resultssupporting

confidence: 64%

Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes

Malouf¹,

Su²,

Yao³

et al. 2014

Clinical Cancer Research

121

106

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Purpose MITF/TFE translocation renal cell carcinoma (TRCC) is a rare subtype of kidney cancer. Its incidence and the genome-wide characterization of its genetic origin have not been fully elucidated. Experimental design We performed RNA and exome sequencing on an exploratory set of TRCC (n=7), and validated our findings using The Cancer Genome Atlas (TCGA) clear-cell RCC (ccRCC) dataset (n=460). Results Using the TCGA dataset, we identified 7 TRCC (1.5%) cases and determined their genomic profile. We discovered three novel partners of MITF/TFE (LUC7L3, KHSRP and KHDRBS2), which are involved in RNA splicing. TRCC displayed a unique gene expression signature as compared to other RCC types, and showed activation of MITF, the transforming growth factor β1 and the PI3K complex targets. Genes differentially spliced between TRCC and other RCC types were enriched for MITF and ID2 targets. Exome sequencing of TRCC revealed a distinct mutational spectrum as compared to ccRCC, with frequent mutations in chromatin remodeling genes (six of eight cases, three of which from the TCGA). In two cases, we identified mutations in INO80D, an ATP-dependent chromatin remodeling gene, previously shown to control the amplitude of the S phase. Knockdown of INO80D decreased cell proliferation in a novel cell line bearing LUC7L3-TFE3 translocation. Conclusions This genome-wide study defines the incidence of TRCC within a ccRCC-directed project and expands the genomic spectrum of TRCC by identifying novel MITF/TFE partners involved in RNA splicing and frequent mutations in chromatin remodeling genes.

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Section: Resultssupporting

confidence: 64%

Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes

Malouf¹,

Su²,

Yao³

et al. 2014

Clinical Cancer Research

121

106

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“…By immunohistochemistry, these tumors frequently underexpress cytokeratins, but frequently express melanocytic markers and the cysteine protease cathepsin k, which distinguishes them from more common RCC subtypes (12–14). Overall, outcome is similar to that of clear cell RCC, with increased age and advanced stage being poor prognostic factors (15,16). While immunohistochemistry for overexpressed TFE3 fusion proteins was initially the only method to confirm this diagnosis in formalin-fixed, paraffin embedded archival material (17), break-apart fluorescence in situ hybridization (FISH) demonstrating TFE3 gene rearrangement is now the preferred method (10, 11,18,19).…”

Section: Introductionmentioning

confidence: 73%

TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers

Argani

Zhong

Reuter

et al. 2016

American Journal of Surgical Pathology

182

221

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Xp11 translocation cancers include Xp11 translocation renal cell carcinoma (RCC), Xp11 translocation perivascular epithelioid cell tumor (PEComa), and melanotic Xp11 translocation renal cancer. In Xp11 translocation cancers, oncogenic activation of TFE3 is driven by the fusion of TFE3 with a number of different gene partners, however, the impact of individual fusion variant on specific clinicopathologic features of Xp11 translocation cancers has not been well defined. In this study, we analyze 60 Xp11 translocation cancers by fluorescence in situ hybridization (FISH) using custom BAC probes to establish their TFE3 fusion gene partner. In 5 cases RNA sequencing (RNA-seq) was also used to further characterize the fusion transcripts. The 60 Xp11 translocation cancers included 47 Xp11 translocation RCC, 8 Xp11 translocation PEComas, and 5 melanotic Xp11 translocation renal cancers. A fusion partner was identified in 53/60 (88%) cases, including 18 SFPQ (PSF), 16 PRCC, 12 ASPSCR1 (ASPL), 6 NONO, and 1 DVL2. We provide the first morphologic description of the NONO-TFE3 RCC, which frequently demonstrates sub-nuclear vacuoles leading to distinctive suprabasal nuclear palisading. Similar sub-nuclear vacuolization was also characteristic of SFPQ-TFE3 RCC, creating overlapping features with clear cell papillary RCC. We also describe the first RCC with a DVL2-TFE3 gene fusion, in addition to an extrarenal pigmented PEComa with a NONO-TFE3 gene fusion. Furthermore, among neoplasms with the SFPQ-TFE3, NONO-TFE3, DVL2-TFE3 and ASPL-TFE3 gene fusions, the RCC are almost always PAX8-positive, cathepsin K-negative by immunohistochemistry, whereas the mesenchymal counterparts (Xp11 translocation PEComas, melanotic Xp11 translocation renal cancers, and alveolar soft part sarcoma) are PAX8-negative, cathepsin K-positive. These findings support the concept that despite an identical gene fusion, the RCCs are distinct from the corresponding mesenchymal neoplasms, perhaps due to the cellular context in which the translocation occurs. We corroborate prior data showing that the PRCC-TFE3 RCC are the only known Xp11 translocation RCC molecular subtype which is consistently cathepsin K positive. In summary, our data expand further the clinicopathologic features of cancers with specific TFE3 gene fusions, and should allow for more meaningful clinicopathologic associations to be drawn.

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“…Xp11.2 tRCC typically affects children and young adults under 45 years of age [3, 4, 19, 20] with a one-third incidence in juveniles and 0.2–5.0% incidence in adults [16, 21–23]. Unlike pediatric RCCs, cytogenetics is not routinely performed for adult RCCs due to the relatively lower incidence rate, which results in most misdiagnoses as conventional RCCs.…”

Section: Discussionmentioning

confidence: 99%

“…Despite its low incidence, Xp11.2 RCC is more harmful than conventional RCC because the majority of patients present at advanced stages and invasive clinical courses [2–5, 16]. Surgical treatment, especially radical nephrectomy (RN), remains the most common strategy to treat Xp11.2 tRCC.…”

Section: Introductionmentioning

confidence: 99%

Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusions: Clinical Features, Treatments and Prognosis

et al. 2016

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To investigate the clinical characteristics, treatments and prognosis of renal cell carcinoma associated with Xp11.2 translocation/TFE3 gene fusions (Xp11.2 tRCC), the epidemiological features and treatment results of 34 cases of Xp11.2 tRCC, which were diagnosed by immunohistochemistry staining of TFE3 and fluorescence in situ hybridization at our center, were retrospectively reviewed. The 34 patients included 21 females and 13 males aged 3 to 64 years (median age: 27 years). Four patients were children or adolescents (<18 years of age), and 26 patients were young or middle-aged adults (18–45 years). Radical nephrectomy was performed on 25 patients. Laparoscopic nephron-sparing surgery was performed on 9 patients who presented with an isolated mass with a small diameter (<7 cm) and well-defined boundary on computed tomography imaging. Postoperative staging showed that 25 cases (73.53%) were at stage I/II, while 9 cases (26.47%) were at stage III/IV. All stage I/II patients received a favorable prognosis with a three-year overall survival rate of 100%, including the patients who underwent laparoscopic nephron-sparing surgery. With the exception of 2 children, the other 7 stage III/IV patients died or developed recurrence with a median follow-up of 29 months. On univariate analysis, maximum diameter, adjuvant treatment, TNM stage, lymph node metastasis, inferior vena cava tumor thrombosis and tumor boundary were identified as statistically significant factors impacting survival (P<0.05). Multivariate analysis indicated that TNM stage and inferior vena cava tumor thrombosis were independent prognostic factors (P<0.05). In conclusion, Xp11.2 tRCC is a rare subtype of renal cell carcinoma that mainly occurs in young females. Nephron-sparing surgery was confirmed effective preliminarily in the treatment of small Xp11.2 tRCCs with clear rims. Advanced TNM stage and inferior vena cava tumor thrombosis were associated with poor prognosis.

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TFE3 Rearrangements in Adult Renal Cell Carcinoma

Cited by 128 publications

References 22 publications

Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes

Next-Generation Sequencing of Translocation Renal Cell Carcinoma Reveals Novel RNA Splicing Partners and Frequent Mutations of Chromatin-Remodeling Genes

TFE3-Fusion Variant Analysis Defines Specific Clinicopathologic Associations Among Xp11 Translocation Cancers

Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusions: Clinical Features, Treatments and Prognosis

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