Factor E3 Research Articles

Novel YAP1‐TFE3 fusion defines a distinct subset of epithelioid hemangioendothelioma

Conventional epithelioid hemangioendotheliomas (EHE) have a distinctive morphologic appearance and are characterized by a recurrent t(1;3) translocation, resulting in a WWTR1-CAMTA1 fusion gene. We have recently encountered a fusion-negative subset characterized by a somewhat different morphology, including focally well-formed vasoformative features, which was further investigated for recurrent genetic abnormalities. Based on a case showing strong transcription factor E3 (TFE3) immunoreactivity, fluorescence in situ hybridization (FISH) analysis for TFE3 gene rearrangement was applied to the index case as well as to nine additional cases, selected through negative WWTR1-CAMTA1 screening. A control group, including 18 epithelioid hemangiomas, nine pseudomyogenic HE, and three epithelioid angiosarcomas, was also tested. TFE3 gene rearrangement was identified in 10 patients, with equal gender distribution and a mean age of 30 years old. The lesions were located in somatic soft tissue in six cases, lung in three and one in bone. One case with available frozen tissue was tested by RNA sequencing and FusionSeq data analysis to detect novel fusions. A YAP1-TFE3 fusion was thus detected, which was further validated by FISH and reverse transcription polymerase chain reaction (RT-PCR). YAP1 gene rearrangements were then confirmed in seven of the remaining nine TFE3-rearranged EHEs by FISH. No TFE3 structural abnormalities were detected in any of the controls. The TFE3-rearranged EHEs showed similar morphologic features with at least focally, well-formed vascular channels, in addition to a variably solid architecture. All tumors expressed endothelial markers, as well as strong nuclear TFE3. In summary, we are reporting a novel subset of EHE occurring in young adults, showing a distinct phenotype and YAP1-TFE3 fusions.

297 ESTABLISHMENT OF A RENAL CELL CARCINOMA CELL LINE ASSOCIATED WITH TFE3 GENE FUSIONS

INTRODUCTION AND OBJECTIVES: Xp11.2 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. It has been recently recognized as a subtype of renal cell carcinoma primarily described in the 2004 World Health Organization classification of renal tumors, and various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome cause the tumor; however, little is known about the tumor characteristics. We report the cytogenetic and biological characteristics of a renal cell carcinoma cell line with TFE3 gene fusion established from a young female with locally advanced renal cell carcinoma. METHODS: Tumor cells were obtained from a renal tumor in a 16-year-old Japanese female. This primary tumor was pathologically diagnosed as renal cell carcinoma with Xp11 translocations. After cultured in vitro, cell suspension was inoculated into the nude mice to establish xenograft. TFE3 immunostaining and other immunohistochemistries were performed. Molecular and cytogenetic methods such as RT-PCR, karyotype analysis and FISH were added. RESULTS: The established cell line and its xenograft showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis, and ASPLTFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Multicolor FISH analysis showed more complicated rearrangements on the chromosome than expected. CONCLUSIONS: Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. This cell line will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.

Transcription Factor E3 Protein–Positive Perivascular Epithelioid Cell Tumor of the Appendix Presenting as Acute Appendicitis: A Case Report and Review of the Literature

Perivascular epithelioid cell tumors (PEComas) are a group of mesenchymal tumors that coexpress melanocytic and smooth muscle markers; their exact origin remains unknown. This group includes renal angiomyolipoma, clear cell sugar tumor, and lymphangioleiomyomatosis, although the term perivascular epithelioid cell tumors is currently used for lesions that exhibit a similar morphologic and immunohistochemical profile throughout the human body. Recently, a distinct subset of PEComas has been shown to harbor transcription factor E3 gene (TFE3) fusions. We report, for the first time, a unique case of TFE3-positive PEComa presenting as acute appendicitis in a 24-year-old woman. Microscopically, the tumor was composed of benign-appearing epithelioid cells with clear and eosinophilic cytoplasm, and arranged in nested and alveolar patterns. Immunohistochemical studies showed diffuse strong positivity for neuron-specific enolase, TFE3, and progesterone receptor and focal strong positivity for human melanoma black-45 (HMB-45) and melanocyte differentiation antigen (Melan-A) in the tumor cells. Although rare, PEComa should be included in the differential diagnosis of mesenchymal tumors of the appendix.

Cathepsin K expression in a wide spectrum of perivascular epithelioid cell neoplasms (PEComas): a clinicopathological study emphasizing extrarenal PEComas

Recent studies have demonstrated that cathepsin K seems to be a powerful marker in identifying renal perivascular epithelioid cell neoplasms (PEComas). However, the expression in extrarenal PEComas has not been well characterized due to their rare incidence. Our aim was to investigate the expression of cathepsin K in a wide spectrum of extrarenal PEComas and evaluate its potential diagnostic usefulness in comparison with other commonly used markers. Twenty-three cases of PEComa (liver, n = 9; lung, n = 1; broad ligament of uterus, n = 1; vertex subcutaneous soft tissue, n = 1; abdominal wall, n = 1; and kidney, n = 10) were selected for study. All displayed a high percentage of cells with moderately to strongly positive reactions for cathepsin K (mean 91%; range 80-100%). HMB45, Melan-A and smooth muscle actin (SMA) were expressed in 78, 87 and 87% of cases, respectively, with various percentages of positive cells (mean, 34, 40 and 38%; range 0-80, 0-90 and 0-90%). Transcription factor E3 (TFE3) was expressed strongly in only three cases; none exhibited evidence of TFE3 gene fusion or amplification. Cathepsin K appears to be more powerful than other commonly used markers in diagnosing a wide spectrum of PEComas and distinguishing them from the majority of human cancers.

Renal Cell Carcinoma Associated with Xp11.2 Translocation/Transcription Factor E3 (TFE3) Fusion

Renal cell carcinomas (RCC) associated with Xp11.2 translocations (Xp11.2 TRCCs) form a new and little known entity of the WHO 2004 classification [1-23]. de Jong et al. [1] and Tomlinson et al [2] first described Xp11 translocation as a previously unknown finding in the karyotype of two atypical renal masses presenting in infant males [13]. These neoplasms are defined by several translocations involving the transcription factor 3 (TFE3) gene that is located on chromosome Xp11.2, resulting in a gene fusion between TFE3 and at least 5 possible partners [3-7,16,18,21,23]. These include a distinctive RCC which bears a translocation with the identical chromosomal breakpoints (Xp11.2, 17q25) and identical resulting ASPL-TFE3 gene fusion as alveolar soft part sarcoma (ASPS), with the distinction that the t(X;17) translocation is cytogenetically balanced in these renal tumors [4]. The most commonly observed translocations are t(X;17)(p11.2;q25), t(X;1) (p11.2;p34), and t(X;1)(p11.2;q21), which lead to gene fusions of TFE3 with ASPL, PSF, and PRCC, respectively [3,15,16]. This review aims to highlight the helpful histologic, immunohistochemical, and cytogenetic features of this entity to enable correct diagnosis.

Renal Cell Carcinoma Associated with Xp11.2 Translocation/TFE3 Gene Fusion: A Rare Case Report with Review of the Literature

Introduction. The recently recognized renal cell carcinomas associated with Xp11.2 translocations are rare tumors predominantly reported in children. Chromosome Xp11.2 translocation results in gene fusion related to transcription factor E3 (TFE3) that plays an important role in proliferation and survival. Case Report. Herein, we present two cases of a TFE3 translocation-associated RCC in young female adults, one detected incidentally and the other one presenting with gross hematuria. Tumor is characterized by immunohistochemistry and a literature review with optimal treatment regimen is presented. Discussion. Xp11.2 translocation RCCs in adult patients are associated with advanced stages, large tumors, and extracapsular disease and usually have an aggressive clinical course. Conclusion. In TFE3 RCC, the genetic background may not only contribute to tumorigenesis, but also determine the response to chemotherapy and targeted therapy. Therefore it is necessary to diagnose this tumor entity accurately. Because of the small number of TFE3 gene fusion-related renal tumors described in the literature, the exact biologic behavior and impact of current treatment modalities remain to be uncertain.

Persistent Complete Response After Single-agent Sunitinib Treatment in a Case of TFE Translocation Positive Relapsed Metastatic Pediatric Renal Cell Carcinoma

Forty percent of renal cell carcinomas (RCCs) in childhood are characterized by translocation involving transcription factor E3 (TFE3) family members. Here, we describe a case of TFE3-positive RCC in which metastatic relapse to the mediastinal lymph nodes and pulmonary nodules was treated with single-agent sunitinib, a multitargeted tyrosine inhibitor. Complete radiologic remission was achieved after only 3 courses of treatment, and surgical exploration of metastases failed to identify any residual viable disease. The published experience of sunitinib in TFE-RCC is limited, and prospective evaluation of its activity in a larger number of patients is warranted.

Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver

Transcription factor E3 (TFE3) has been shown to increase insulin sensitivity by activating insulin-signalling pathways. However, the role of TFE3 in glucose homeostasis is not fully understood. Here, we explored the possible therapeutic potential of TFE3 for the control of hyperglycaemia using a streptozotocin-induced mouse model of diabetes. We achieved overabundance of TFE3 in streptozotocin mice by administering an adenovirus (Ad) or adeno-associated virus serotype 2 (AAV2). We also performed an oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). To explore molecular mechanisms of blood glucose control by TFE3, transcriptional studies on the regulation of genes involved in hepatic glucose metabolism were performed using quantitative real-time PCR and chromatin immunoprecipitation assay. The binding site of TFE3 in the liver Gck gene promoter was identified using deletion and site-specific mutation studies. Overabundance of TFE3 resulted in reduced hyperglycaemia as shown by the OGTT and ITT in streptozotocin-treated mice. We observed that TFE3 can upregulate Gck in a state of insulin deficiency. However, glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase mRNA levels were decreased by Ad-mediated overexpression of Tcfe3. Biochemical studies revealed that the anti-hyperglycaemic effect of TFE3 is due to the upregulation of Gck. In primary cultured hepatocytes, TFE3 increased expression of Gck mRNA. Conversely, small interfering RNA-mediated knockdown of TFE3 resulted in a decrease in Gck mRNA. This study demonstrates that TFE3 counteracts hyperglycaemia in streptozotocin-treated mice. This effect could be due to the upregulation of Gck by binding of TFE3 to its cognitive promoter region.

TFE3 inhibits myoblast differentiation in C2C12 cells via down-regulating gene expression of myogenin

Transcription factor E3 (TFE3) belongs to a basic helix–loop–helix family, and is involved in the biology of osteoclasts, melanocytes and their malignancies. We previously reported the metabolic effects of TFE3 on insulin in the liver and skeletal muscles in animal models. In the present study, we explored a novel role for TFE3 in a skeletal muscle cell line. When TFE3 was overexpressed in C2C12 myoblasts by adenovirus before induction of differentiation, myogenic differentiation of C2C12 cells was significantly inhibited. Adenovirus-mediated TFE3 overexpression also suppressed the gene expression of muscle regulatory factors (MRFs), such as MyoD and myogenin, during C2C12 differentiation. In contrast, knockdown of TFE3 using adenovirus encoding short-hairpin RNAi specific for TFE3 dramatically promoted myoblast differentiation associated with significantly increased expression of MRFs. Consistent with these findings, promoter analyses via luciferase reporter assay and electrophoretic mobility shift assay suggested that TFE3 negatively regulated myogenin promoter activity by direct binding to an E-box, E2, in the myogenin promoter. These findings indicated that TFE3 has a regulatory role in myoblast differentiation, and that transcriptional suppression of myogenin expression may be part of the mechanism of action.

Rapidly progressing renal cell carcinoma associated with Xp11.2 translocations: a case report

IntroductionRenal cell carcinoma associated with Xp11.2 translocations is frequently reported in children, but adult-onset is rare. Here, the case of an adult male who developed a renal cell carcinoma associated with Xp11.2 translocations is presented.Case presentationA 38-year-old Asian man presented with left back pain and macroscopic hematuria. Computed tomography revealed a left renal tumor (T3N2M0), and a left radical nephrectomy was performed. Hematoxylin-eosin staining revealed papillary architecture and clear or eosinophilic cytoplasm, and the diagnosis of renal cell carcinoma associated with Xp11.2 translocations/TFE3 gene fusion was made by the immunohistochemical determination of transcription factor E3 protein. In spite of adjuvant therapy with α-interferon, a recurrent tumor was found in his left lung by computed tomography three months after the nephrectomy. Interleukin-2, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors showed no effect on tumor progression.ConclusionsRenal cell carcinomas associated with Xp11.2 translocations have an aggressive clinical course in adults. Strict diagnosis using the immunohistochemistry of transcription factor E3 protein is important to predict the prognosis of such patients and new strategies need to be determined to treat patients with these tumors

A transcriptional network underlies susceptibility to kidney disease progression

The molecular networks that control the progression of chronic kidney diseases (CKD) are poorly defined. We have recently shown that the susceptibility to development of renal lesions after nephron reduction is controlled by a locus on mouse chromosome 6 and requires epidermal growth factor receptor (EGFR) activation. Here, we identified microphthalmia-associated transcription factor A (MITF-A), a bHLH-Zip transcription factor, as a modifier of CKD progression. Sequence analysis revealed a strain-specific mutation in the 5′ UTR that decreases MITF-A protein synthesis in lesion-prone friend virus B NIH (FVB/N) mice. More importantly, we dissected the molecular pathway by which MITF-A modulates CKD progression. MITF-A interacts with histone deacetylases to repress the transcription of TGF-α, a ligand of EGFR, and antagonizes transactivation by its related partner, transcription factor E3 (TFE3). Consistent with the key role of this network in CKD, Tgfa gene inactivation protected FVB/N mice from renal deterioration after nephron reduction. These data are relevant to human CKD, as we found that the TFE3/MITF-A ratio was increased in patients with damaged kidneys. Our study uncovers a novel transcriptional network and unveils novel potential prognostic and therapeutic targets for preventing human CKD progression.

Translocation renal cell carcinomas: An evolving entity.

e15078 Background: Translocation renal cell carcinomas (tRCCs) are a novel, rare and distinct clinicopathological entity. The term refers to RCCs with overexpression of transcription factor E3 (TFE3) due to translocation involving the Xp11 locus or less commonly with overexpression of transcription factor EB (TFEB) due to a t(6:11) translocation. In children it is estimated that these tumours account for 40% of RCCs but in adults this proportion is estimated to be 1-4%. These neoplasms are only recently recognised and outcome data are premature. We report 2 cases of tRCC in an Irish regional cancer centre and describe clinicopathological characteristics and early outcome. Methods: : Approximately 70 new cases of RCC are referred to our centre annually. Recently, 2 renal cell carcinomas were suspected to be tRCCs on morphology and immunohistochemical(IHC) features (RCC+/CK7-/EMA-). Using IHC we tested for expression of TFE3 and TFEB. Results: : Both tumours were tRCCs. The first case was a 74 year old lady who presented with right upper quadrant pain and had a 9cm right renal mass with no metastatic disease on CT imaging. Radical nephrectomy was performed and histology revealed a pT3aN2, Fuhrman grade 4 RCC with mixed clear cell and papillary architecture. IHC for TFE3 showed focal nuclear positivity consistent with an Xp11 translocation RCC. She relapsed 9 months later with local recurrence, retroperitoneal adenopathy and lung metastases. She commenced sunitinib and response assessment is pending. The 2nd case was a 46 year old man with an incidental finding of a right renal mass on ultrasound abdomen. Staging CT revealed no metastatic disease and he underwent laparoscopic nephrectomy. Histology revealed a pT1aNx, Fuhrman grade 3 renal cell carcinoma with predominantly alveolar architecture and focal papillary and microcystic areas. IHC for TFEB was positive consistent with a t6:11 translocation RCC. He remains disease free 9 months post surgery. Conclusions: We report 2 new cases of this rare subset of RCC. The therapeutic implications for patients with these mutations are as yet unclear. We plan to update with ongoing follow-up and will also report 3 further cases suspected to be tRCCs based on morphology and IHC. Confirmatory TFE3/TFEB IHC is awaited.

Long-term outcomes of children with Xp11.2 translocation renal cell carcinoma.

9569 Background: We aimed to assess the clinico-pathological characteristics and the long-term prognosis of Xp11.2 translocation renal cell carcinoma (Xp-RCC) in children. Methods: A total of 52 Japanese children with renal tumors were presented to our institutions. Of these, 5 (10%) had RCC, and all RCCs were Xp11.2 translocation subtype with positive nuclear transcription factor E3 immunostaining. We retrospectively reviewed the pathological and hospital records of these 5 patients. Results: In the 1 boy and 4 girls with an average age of 9 years 7 months at diagnosis, the most common presenting complains were gross hematuria (60%) and palpable abdominal mass (40%). All patients had unilateral disease and there was no special family or medical history in any children. Computerized tomography revealed characteristic calcification within the tumor in 4 of the 5 patients (80%). In the remaining case, the lesion had high density areas with microcalcification, as confirmed by histopathological study. In 3 patients with regional lymph node metastasis, calcification was also observed in the metastatic lesions. Stage of the disease were stage I in 1 patient, II in 1, IV without and with distant metastasis in 2 and 1, respectively. All patients underwent transabdominal nephrectomy with regional lymphadenectomy. One patient with stage I disease had multiple metastases 15 months after surgery and died of disease in spite of interferon and chemotherapy 4 years postoperatively. Three patients received adjuvant interferon therapy and 2 of them are without evidence of recurrence postoperative 19 and 14 years, respectively. One of them had lymph node and lung metastases 12 years postoperatively. The remaining one patient had multiple lymph node, lung, bone, and dura mater metastases at diagnosis. The latter 2 patients have received targeted therapy (sunitinib, temsirolimus) without their progression for 6 and 12 months, respectively. Conclusions: Calcification within the tumor and/or metastatic lesions is characteristic findings suggestive of Xp-RCC in children. Regional lymphadenectomy or targeted therapy may provide some benefit in selected pediatric patients. Long-term follow-up is essential in pediatric patients with RCC.

Renal Cell Carcinoma Associated With Transcription Factor E3 Expression and Xp11.2 Translocation

We studied the characteristics and prognosis of renal cell carcinoma (RCC) associated with Xp11.2 translocation and transcription factor E3 (TFE3) expression and determined the need for genetic analysis in routine diagnostics. Of 848 consecutive cases, 75 showed microscopic features suggestive of Xp11.2 translocation RCC or occurred in patients 40 years or younger. Of these cases, 17 (23%) showed strong nuclear TFE3 immunostaining, which was associated with more advanced tumors and inverse prognosis in univariate (P = .032) but not multivariate (P = .404) analysis. With fluorescence in situ hybridization and polymerase chain reaction, only 2 cases showed alterations of the X chromosome and the ASPL-TFE3 gene fusion, respectively. In our laboratory, the predictive value of TFE3 expression for the Xp11.2 translocation was 12%. Strong nuclear TFE3 expression is associated with metastatic spread and a poor prognosis. In our laboratory, TFE3 is not diagnostic for Xp11.2 translocation RCC. Diagnosis of Xp11.2 translocation RCC may be made only genetically.

153 CARBONIC ANHYDRASE XII: POTENTIAL ROLE IN LYMPHATIC METASTASES OF RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research I1 Apr 2012153 CARBONIC ANHYDRASE XII: POTENTIAL ROLE IN LYMPHATIC METASTASES OF RENAL CELL CARCINOMA Nnenaya Agochukwu, Kiranpreet Khurana, Eric Kauffman, Brian Shuch, Vladimir Valera, Youfeng Yang, W. Marston Linehan, and Gennady Bratslavsky Nnenaya AgochukwuNnenaya Agochukwu Bethesda, MD More articles by this author , Kiranpreet KhuranaKiranpreet Khurana Cleveland, OH More articles by this author , Eric KauffmanEric Kauffman Bethesda, MD More articles by this author , Brian ShuchBrian Shuch Bethesda, MD More articles by this author , Vladimir ValeraVladimir Valera Bethesda, MD More articles by this author , Youfeng YangYoufeng Yang Bethesda, MD More articles by this author , W. Marston LinehanW. Marston Linehan Bethesda, MD More articles by this author , and Gennady BratslavskyGennady Bratslavsky Syracuse, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.203AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Metastasis in renal cell carcinoma (RCC) is a major predictor of survival, yet little is known about metastasis of RCC to the lymph nodes. Using matched pairs of cell lines derived from patients with a primary tumor of RCC origin and sites of lymph nodal metastasis also of RCC origin, we sought to investigate the potential differences between the lymph node metastasic site and the primary site in tumor cell lines derived from the same patients. METHODS The cell lines used for this analysis were obtained from the Urologic Oncology Branch of the NCI cell repository and included 3 pairs with the von Hippel- Lindau (VHL) mutation and 1 pair with a mutation in the Transcription factor E3 (TFE3) gene. Each pair represents one patient. Sequencing and fingerprinting were done to confirm that the origin of each pair of cell lines were from the same patient. Gene expression microarrays using an affymetrix platform followed by Real Time Polymerase Chain Reaction (RT-PCR) were done to confirm the differentially expressed genes. Western blot was subsequently done to confirm RT-PCR findings using a monocolonal antibody. RESULTS Sequencing and fingerprinting confirmed that the matched pair cell lines were from the same patient. Microarray gene expression array demonstrated differential expression of several genes with Carbonic Anhydrase XII (CAXII) overexpression in metastatic cell lines in 3 different probes with up to 4 fold difference. RT-PCR confirmed our microarray findings with increased expression of CAXII in the cell lines derived from sites of lymph nodal metastases. Western blot analysis confirmed increased expression of the CAXII protein for the metastatic cell lines when compared to cell lines derived from the primary tumors. CONCLUSIONS The present results demonstrate that CAXII has increased expression in metastatic RCC as compared to primary RCC from the matched cell lines. Such findings may be due to adaptation to the lymph node environment and provide an explanation for the mechanism that metastatic cells employ to survive in the lymph environment thereby avoiding the recognition or destruction by the immune cells. Further assays will be performed to better elucidate the role of CAXII in lymph node metastases. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e63 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Nnenaya Agochukwu Bethesda, MD More articles by this author Kiranpreet Khurana Cleveland, OH More articles by this author Eric Kauffman Bethesda, MD More articles by this author Brian Shuch Bethesda, MD More articles by this author Vladimir Valera Bethesda, MD More articles by this author Youfeng Yang Bethesda, MD More articles by this author W. Marston Linehan Bethesda, MD More articles by this author Gennady Bratslavsky Syracuse, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Transcription factor E3, a major regulator of mast cell–mediated allergic response

Microphthalmia transcription factor, an MiT transcription family member closely related to transcription factor E3 (TFE3), is essential for mast cell development and survival. TFE3 was previously reported to play a role in the functions of B and T cells; however, its role in mast cells has not yet been explored. We sought to explore the role played by TFE3 in mast cell function. Mast cell numbers were evaluated by using toluidine blue staining. FACS analysis was used to determine percentages of Kit and FcεRI double-positive cells in the peritoneum of wild-type (WT) and TFE3 knockout (TFE3(-/-)) mice. Cytokine and inflammatory mediator secretion were measured in immunologically activated cultured mast cells derived from either knockout or WT mice. In vivo plasma histamine levels were measured after immunologic triggering of these mice. No significant differences in mast cell numbers between WT and TFE3(-/-) mice were observed in the peritoneum, lung, and skin. However, TFE3(-/-) mice showed a marked decrease in the number of Kit(+) and FcεRI(+) peritoneal and cultured mast cells. Surface expression levels of FcεRI in TFE3(-/-) peritoneal mast cells was significantly lower than in control cells. Cultured mast cells derived from TFE3(-/-) mice showed a marked decrease in degranulation and mediator secretion. In vivo experiments showed that the level of plasma histamine in TFE3(-/-) mice after an allergic trigger was substantially less than that seen in WT mice. TFE3 is a novel regulator of mast cell functions and as such could emerge as a new target for the manipulation of allergic diseases.

Translocation renal cell carcinomas: An evolving entity.

472 Background: Translocation renal cell carcinomas (RCCs) are a novel, rare and distinct clinicopathological entity. The term refers to RCCs with overexpression of transcription factor E3 (TFE3) due to translocation involving the Xp11 locus or less commonly with overexpression of transcription factor EB (TFEB) due to a t(6:11) translocation. In children it is estimated that these tumours account for 40% of RCCs but in adults this proportion is estimated to be 1-4%. As these neoplasms are only recently recognised, outcome data are premature. We report 2 cases of translocation RCC in an Irish regional cancer centre and describe clinicopathological characteristics and early outcome. Methods: In our recent practice, 2 renal cell carcinomas were suspected to be translocation tumours based on morphology and immunohistochemical features (RCC+/CK7-/EMA-). Using immunohistochemistry we tested for expression of TFE3 and TFEB. Results: Both tumours were translocation RCCs. The first case was a 74 year old lady who presented with right upper quadrant pain and had a 9cm right renal mass with no metastatic disease on CT imaging. Radical nephrectomy was performed and histology revealed a pT3aN2, Fuhrman grade 4 renal cell carcinoma with papillary architecture and eosinophillic hyaline nodules within many of the papillae. Staining for TFE3 showed focal nuclear positivity consistent with an Xp11 translocation RCC. She remains disease free 6 months post surgery. The second case was a 46 year old man with an incidental finding of a right renal mass on ultrasound abdomen performed after a new diagnosis of haemochromatosis. Staging CT imaging revealed no metastatic disease and he underwent laparoscopic nephrectomy. Histology revealed a pT1aNx, Fuhrman grade 3 renal cell carcinoma with predominantly alveolar architecture and focal papillary and microcystic areas. Staining for TFEB was positive consistent with a t6:11 translocation RCC. He remains disease free 5 months post surgery. Conclusions: We report 2 new cases of this rare subset of RCC. The therapeutic implications for patients with these mutations are as yet unclear. We plan to update with ongoing follow-up and identification of new cases to determine the clinical behaviour of these rare cancers in the Irish setting.

Ovarian perivascular epithelioid cell tumor not otherwise specified with transcription factor E3 gene rearrangement: a case report and review of the literature

We report the first case of isolated ovarian perivascular epithelioid cell tumor not otherwise specified in a 33-year-old woman with no history of tuberous sclerosis. A right ovary specimen revealed a well-circumscribed 2.5 × 2 cm solid mass. Microscopically, the mass was composed of nests of tumor cells that were separated by fibrous septa. The tumor cells were composed of pure epithelioid cells with abundant clear cytoplasm and dark brown pigments. Immunohistochemically, the tumor cells showed diffuse and strong cytoplasmic staining of HMB45; however, the tumor cells were not reactive for smooth muscle actin, desmin, inhibin-α, calretinin, and carcinoembryonic antigen. Strong nuclear expression of transcription factor E3 protein was observed in most tumor cells, and transcription factor E3 fluorescence in situ hybridization showed transcription factor E3 rearrangements associated with balanced Xp11 translocations.

TFE3 regulates muscle metabolic gene expression, increases glycogen stores, and enhances insulin sensitivity in mice

The role of transcription factor E3 (TFE3), a bHLH transcription factor, in immunology and cancer has been well characterized. Recently, we reported that TFE3 activates hepatic IRS-2 and hexokinase, participates in insulin signaling, and ameliorates diabetes. However, the effects of TFE3 in other organs are poorly understood. Herein, we examined the effects of TFE3 on skeletal muscle, an important organ involved in glucose metabolism. We generated transgenic mice that selectively express TFE3 in skeletal muscles. These mice exhibit a slight acceleration in growth prior to adulthood as well as a progressive increase in muscle mass. In TFE3 transgenic muscle, glycogen stores were more than twofold than in wild-type mice, and this was associated with an upregulation of genes involved in glucose metabolism, specifically glucose transporter 4, hexokinase II, and glycogen synthase. Consequently, exercise endurance capacity was enhanced in this transgenic model. Furthermore, insulin sensitivity was enhanced in transgenic mice and exhibited better improvement after 4 wk of exercise training, which was associated with increased IRS-2 expression. The effects of TFE3 on glucose metabolism in skeletal muscle were different from that in the liver, although they did, in part, overlap. The potential role of TFE3 in regulating metabolic genes and glucose metabolism within skeletal muscle suggests that it may be used for treating metabolic diseases as well as increasing endurance in sport.

Sunitinib-induced Nephrotic Syndrome in Association with Drug Response in a Patient with Xp11.2 Translocation Renal Cell Carcinoma

We report the case of a patient with metastatic renal cell carcinoma with Xp11.2 translocation/transcription factor E3 (TFE3) gene fusion who had presented with sunitinib-induced nephrotic syndrome in association with favorable and durable treatment response. The nephrotic syndrome was managed successfully by discontinuing sunitinib and symptomatic treatment. The 27-year-old female patient presenting with right upper abdominal pain was diagnosed with Xp11.2 translocation renal cell carcinoma on the right side with multiple pulmonary and hepatic metastases. She underwent radical nephrectomy and took a daily dose of 37.5 mg sunitinib. Partial response to sunitinib was achieved and maintained for 5 months, but when nephrotic syndrome occurred, drug intake was discontinued. The nephrotic syndrome gradually resolved around 2 months after discontinuation of sunitinib and medical management. Our case highlighted the favorable response of a particular non-clear cell type renal cell carcinoma to sunitinib and the specific toxicity associated with the antiangiogenic effect of sunitinib.