ASPSCR1

Gene Summary

Gene:ASPSCR1; ASPSCR1, UBX domain containing tether for SLC2A4
Aliases: TUG, ASPL, ASPS, RCC17, UBXD9, UBXN9, ASPCR1
Location:17q25.3
Summary:The protein encoded by this gene contains a UBX domain and interacts with glucose transporter type 4 (GLUT4). This protein is a tether, which sequesters the GLUT4 in intracellular vesicles in muscle and fat cells in the absence of insulin, and redistributes the GLUT4 to the plasma membrane within minutes of insulin stimulation. Translocation t(X;17)(p11;q25) of this gene with transcription factor TFE3 gene results in a ASPSCR1-TFE3 fusion protein in alveolar soft part sarcoma and in renal cell carcinomas. Multiple alternatively spliced transcript variants have been found. [provided by RefSeq, Oct 2011]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:tether containing UBX domain for GLUT4
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (12)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Kidney CancerASPSCR1 and Kidney Cancer View Publications18
Soft Tissue SarcomaASPSCR1 and Soft Tissue Cancers View Publications8
Lung CancerASPSCR1 and Lung Cancer View Publications5
Brain Tumours, ChildhoodASPSCR1 and Brain Tumours View Publications2
Soft Tissue Sarcomader(17)t(X;17)(p11.2;q25) in Alveolar Soft-Part Sarcoma
der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL 17q25

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: ASPSCR1 (cancer-related)

Yu L, Li J, Xu S, et al.
An Xp11.2 translocation renal cell carcinoma with SMARCB1 (INI1) inactivation in adult end-stage renal disease: a case report.
Diagn Pathol. 2016; 11(1):98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Xp11.2 translocation/transcription factor E3 (TFE3) rearrangement renal cell carcinoma (RCC) is a rare subtype of RCC with limited clinical and pathological data.
CASE PRESENTATION: Here we present an unusual high-grade Xp11.2 translocation RCC with a rhabdoid feature and SMARCB1 (INI1) inactivation in a 40-year-old man with end-stage kidney disease. The histological examination of the dissected left renal tumor showed an organoid architecture of the eosinophilic or clear neoplastic cells with necrosis and high mitotic activity. In some areas, non-adhesive tumor cells with eccentric nuclei were observed. Immunohistochemically (IHC), the tumor cells are positive for TFE3 and the renal tubular markers (PAX2 and PAX8), and completely negative for SMARCB1, an oncosuppressor protein. Break-apart florescence in situ hybridization and reverse transcription polymerase chain reaction confirmed TFE3 rearrangement on Xp11.2 and the presence of ASPSCR1-TFE3 fusion gene. DNA sequencing revealed a frameshift mutation in exon 4 of SMARCB1 gene.
CONCLUSION: It is important to recognize this rare RCC with both TFE3 rearrangement and SMARCB1 inactivation, as the prognosis and therapeutic strategies, particularly targeted therapies for such tumors, might be different.

Just PA, Letourneur F, Pouliquen C, et al.
Identification by FFPE RNA-Seq of a new recurrent inversion leading to RBM10-TFE3 fusion in renal cell carcinoma with subtle TFE3 break-apart FISH pattern.
Genes Chromosomes Cancer. 2016; 55(6):541-8 [PubMed] Related Publications
Gene fusions involving TFE3 defines the "Xp11.2 translocations" subclass of renal cell carcinomas (RCCs) belonging to the MiT family translocation RCC. Four recurrent TFE3 fusion partners were identified to date: PRCC, ASPSCR1, SFPQ, and NONO. Break-apart TFE3 fluorescence in situ hybridization (FISH) on formalin-fixed and paraffin-embedded (FFPE) tissue sections is currently the gold standard for identification of TFE3 rearrangements. Herein, we report a case of RCC with a morphological appearance of Xp11.2 translocation, and positive TFE3 immunostaining. By FISH, the spots constituting the split signal were barely spaced, suggestive of a chromosome X inversion rather than a translocation. We performed RNA-seq from FFPE material to test this hypothesis. RNA-seq suggested a fusion of RBM10 gene exon 17 (Xp11.23) with TFE3 gene exon 5 (Xp11.2). RBM10-TFE3 fusion transcript was confirmed using specific RT-PCR. Our work showed that RNA-Seq is a robust technique to detect fusion transcripts from FFPE material. A RBM10-TFE3 fusion was previously described in single case of Xp11.2 RCC. Although rare, RBM10-TFE3 fusion variant (from chromosome X paracentric inversion), therefore, appears to be a recurrent molecular event in Xp11.2 RCCs. RBM10-TFE3 fusion should be added in the list of screened fusion transcripts in targeted molecular diagnostic multiplex RT-PCR. © 2016 Wiley Periodicals, Inc.

Pradhan D, Roy S, Quiroga-Garza G, et al.
Validation and utilization of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinoma and alveolar soft part sarcoma.
Diagn Pathol. 2015; 10:179 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Xp11.2 or TFE3 translocation renal cell carcinomas (RCC) and alveolar soft part sarcoma (ASPS) are characterized by chromosome translocations involving the Xp11.2 breakpoint resulting in transcription factor TFE3 gene fusions. The most common translocations documented in TFE3 RCCs are t(X;1) (p11.2;q21) and t(X;17) (p11.2;q25) which leads to fusion of TFE3 gene on Xp11.2 with PRCC or ASPL respectively. TFE3 immunohistochemistry (IHC) has been inconsistent over time due to background staining problems in part related to fixation issues. Karyotyping to detect TFE3 gene rearrangement requires typically unavailable fresh tissue. Reverse transcriptase-polymerase chain reaction (RT-PCR) is generally very challenging due to degradation of RNA in archival material. The study objective was to develop and validate a TFE3 break-apart fluorescence in situ hybridization (FISH) assay to confirm Xp11 translocation RCCs and ASPS.
METHODS: Representative sections of formalin-fixed paraffin-embedded tissue blocks were selected in 40 possible cases. Approximately 60 tumor cells were analyzed in the targeted region. The validation of TFE3 FISH was done with 11 negative and two positive cases. Cut off for a positive result was validated as >7.15 % positive nuclei with any pattern of break-apart signals. FISH evaluation was done blinded of the immunohistochemical or karyotype data.
RESULTS: Three out of forty cases were positive for the TFE3 break-apart signals by FISH. The negative cases were reported as clear cell RCC with papillary features (10), clear cell RCC with sarcomatoid areas (2), Papillary RCC with clear cell areas (9), Chromophobe RCC (2), RCC, unclassified type (3) and renal medullary carcinoma (1). 3 of the negative cases were consultation cases for renal tumor with unknown histology. Seven negative cases were soft tissue tumor suspicious for ASPS.
CONCLUSION: Our study validates the utility of TFE3 break-apart FISH on formalin-fixed paraffin-embedded tissue sections for diagnosis and confirmation of Xp11.2 translocation RCCs and ASPS.

Zhao M, Rao Q, Wu C, et al.
Alveolar soft part sarcoma of lung: report of a unique case with emphasis on diagnostic utility of molecular genetic analysis for TFE3 gene rearrangement and immunohistochemistry for TFE3 antigen expression.
Diagn Pathol. 2015; 10:160 [PubMed] Free Access to Full Article Related Publications
Alveolar soft part sarcoma (ASPS) is a rare, malignant mesenchymal tumor of distinctive clinical, morphologic, ultrastructural, and cytogenetical characteristics. It typically arises in the extremities of adolescents and young adults, but has also been documented in a number of unusual sites, thus causing diagnostic confusions both clinically and morphologically. The molecular signature of ASPS is a specific der(17)t(X;17)(p11.2;q25) translocation, which results in the fusion of TFE3 transcription factor gene at Xp11.2 with ASPL at 17q25. Recent studies have shown that the ASPL-TFE3 fusion transcript can be identified by reverse-transcriptase polymerase chain reaction analysis and TFE3 gene rearragement can be detected using a dual-color, break apart fluorescence in situ hybridization assay in paraffin-embedded tissue, and the resultant fusion protein can be detected immunohistochemically with antibody directed to the carboxy terminal portion of TFE3. Herein, we report a unique case of ASPS presenting as an asymptomatic mass in the lung of a 48 year-old woman without evidence of a primary soft tissue tumor elsewhere at the time of initial diagnosis. To the best of our knowledge, this is the third report of such cases appearing in the English language literature to date. We emphasize the differential diagnoses engendered by ASPS including a series of tumors involving the lung that have nested and alveolar growth patterns, and both clear and eosinophilic cytoplasm, and demonstrate the utility of molecular genetic analysis for TFE3 rearrangement and immunohistochemistry for TFE3 antigen expression for arriving at accurate diagnosis.

Xu Y, Rao Q, Xia Q, et al.
TMED6-COG8 is a novel molecular marker of TFE3 translocation renal cell carcinoma.
Int J Clin Exp Pathol. 2015; 8(3):2690-9 [PubMed] Free Access to Full Article Related Publications
TFE3 translocation renal cell carcinoma is a highly aggressive malignancy which often occurs primarily in children and young adults. The pathognomonic molecular lesion in this subtype is a translocation event involving the TFE3 transcription factor at chromosome Xp11.2. Hence, the pathological diagnosis of an Xp11.2 translocation RCC is based upon morphology, TFE3 immunohistochemistry, or genetic analyses. However, due to the false-positive immunoreactivity for TFE3 IHC and expensive for TFE3 break-apart FISH assay, additional molecular markers are necessary to help provide early diagnose and individualization treatment. Owing to recent advances in microarray and RNA-Seq, Pflueger et al. have discovered that TMED6-COG8 is dramatically increased in TFE3 translocation RCCs, compared with clear cell RCCs and papillary RCCs, implying that TMED6-COG8 might be a new molecular tumor marker of TFE3 translocation RCCs. To extend this observation, we firstly validated the TMED6-COG8 expression level by qRT-PCR in RCCs including Xp11.2 translocation RCCs (n=5), clear cell RCCs (n=7) and papillary RCCs (n=5). Then, we also examined the expression level of TMED6-COG8 chimera in Xp11.2 translocation alveolar soft part sarcoma. We found that TMED6-COG8 chimera expression level was higher in Xp11.2 translocation RCCs than in ASPS (P<0.05). What's more, the expression levels of TMED6-COG8 chimera in esophagus cancers (n=32), gastric cancers (n=11), colorectal cancers (n=12), hepatocellular carcinomas (n=10) and non-small-cell lung cancers (n=12) were assessed. Unexpectedly, TMED6-COG8 chimera was decreased in these five human types. Therefore, our observations from this study indicated that TMED6-COG8 chimera might act as a novel diagnostic marker in Xp11.2 translocation RCCs.

Chen X, Yang Y, Gan W, et al.
Newly designed break-apart and ASPL-TFE3 dual-fusion FISH assay are useful in diagnosing Xp11.2 translocation renal cell carcinoma and ASPL-TFE3 renal cell carcinoma: a STARD-compliant article.
Medicine (Baltimore). 2015; 94(19):e873 [PubMed] Free Access to Full Article Related Publications
The diagnosis of Xp11.2 translocation renal cell carcinoma (tRCC), which relies on morphology and immunohistochemistry (IHC), is often either missed in the diagnosis or misdiagnosed. To improve the accuracy of diagnosis of Xp11.2 tRCC and ASPL-TFE3 renal cell carcinoma (RCC), we investigated newly designed fluorescence in situ hybridization (FISH) probes (diagnostic accuracy study).Based on the genetic characteristics of Xp11.2 tRCC and the ASPL-TFE3 RCC, a new break-apart TFE3 FISH probe and an ASPL-TFE3 dual-fusion FISH probe were designed and applied to 65 patients with RCC who were <45 years old or showed suspicious microscopic features of Xp11.2 tRCC in our hospital. To test the accuracy of the probes, we further performed reverse transcriptase-polymerase chain reaction (PCR) on 8 cases for which frozen tissues were available.Among the 65 cases diagnosed with RCC, TFE3 IHC was positive in 24 cases. Twenty-two cases were confirmed as Xp11.2 tRCC by break-apart TFE3 FISH, and 6 of these cases were further diagnosed as ASPL-TFE3 RCC by ASPL-TFE3 dual-fusion FISH detection. Importantly, reverse transcriptase-PCR showed concordant results with the results of FISH assay in the 8 available frozen cases.The break-apart and ASPL-TFE3 dual-fusion FISH assay can accurately detect the translocation of the TFE3 gene and ASPL-TFE3 fusion gene and can thus serve as a valid complementary method for diagnosing Xp11.2 tRCC and ASPL-TFE3 RCC.

Goldberg JM, Fisher DE, Demetri GD, et al.
Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines.
Clin Cancer Res. 2015; 21(14):3178-86 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF).
EXPERIMENTAL DESIGN: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week.
RESULTS: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed.
CONCLUSIONS: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.

Goodwin ML, Jin H, Straessler K, et al.
Modeling alveolar soft part sarcomagenesis in the mouse: a role for lactate in the tumor microenvironment.
Cancer Cell. 2014; 26(6):851-62 [PubMed] Free Access to Full Article Related Publications
Alveolar soft part sarcoma (ASPS), a deadly soft tissue malignancy with a predilection for adolescents and young adults, associates consistently with t(X;17) translocations that generate the fusion gene ASPSCR1-TFE3. We proved the oncogenic capacity of this fusion gene by driving sarcomagenesis in mice from conditional ASPSCR1-TFE3 expression. The completely penetrant tumors were indistinguishable from human ASPS by histology and gene expression. They formed preferentially in the anatomic environment highest in lactate, the cranial vault, expressed high levels of lactate importers, harbored abundant mitochondria, metabolized lactate as a metabolic substrate, and responded to the administration of exogenous lactate with tumor cell proliferation and angiogenesis. These data demonstrate lactate's role as a driver of alveolar soft part sarcomagenesis.

Kauffman EC, Ricketts CJ, Rais-Bahrami S, et al.
Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers.
Nat Rev Urol. 2014; 11(8):465-75 [PubMed] Free Access to Full Article Related Publications
Despite nearly two decades passing since the discovery of gene fusions involving TFE3 or TFEB in sporadic renal cell carcinoma (RCC), the molecular mechanisms underlying the renal-specific tumorigenesis of these genes remain largely unclear. The recently published findings of The Cancer Genome Atlas Network reported that five of the 416 surveyed clear cell RCC tumours (1.2%) harboured SFPQ-TFE3 fusions, providing further evidence for the importance of gene fusions. A total of five TFE3 gene fusions (PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3, and CLTC-TFE3) and one TFEB gene fusion (MALAT1-TFEB) have been identified in RCC tumours and characterized at the mRNA transcript level. A multitude of molecular pathways well-described in carcinogenesis are regulated in part by TFE3 or TFEB proteins, including activation of TGFβ and ETS transcription factors, E-cadherin expression, CD40L-dependent lymphocyte activation, mTORC1 signalling, insulin-dependent metabolism regulation, folliculin signalling, and retinoblastoma-dependent cell cycle arrest. Determining which pathways are most important to RCC oncogenesis will be critical in discovering the most promising therapeutic targets for this disease.

Jabbour MN, Seoud M, Al-Ahmadie H, et al.
ASPL-TFE3 translocation in vulvovaginal alveolar soft part sarcoma.
Int J Gynecol Pathol. 2014; 33(3):263-7 [PubMed] Related Publications
Alveolar soft part sarcoma of the vulvovaginal region is limited to only 8 reported vaginal cases and 1 vulvar case in the English literature. The histogenesis of the tumor remains intriguing with postulates favoring a myogenic versus nonmyogenic origin. A reciprocal translocation for ASPL-TFE3 gene fusion, frequently detected in ~90% of cases, combined with TFE3 protein immunoexpression are highly sensitive and specific methods for diagnostic confirmation. The current report describes a unique case of vulvovaginal alveolar soft part sarcoma showing the classic morphologic features with documentation of TFE3 protein expression and the ASPL-TFE3 gene rearrangement. Furthermore, a brief review of the literature of vulvar and vaginal alveolar soft part sarcoma cases with the various treatment modalities is outlined.

Kubota D, Yoshida A, Kawai A, Kondo T
Proteomics identified overexpression of SET oncogene product and possible therapeutic utility of protein phosphatase 2A in alveolar soft part sarcoma.
J Proteome Res. 2014; 13(5):2250-61 [PubMed] Related Publications
Alveolar soft part sarcoma (ASPS) is an exceedingly rare sarcoma refractory to standard chemotherapy. Although several molecular targeting drugs have been applied for ASPS, their clinical significance has not yet been established, and novel therapeutic strategies have long been required. The aim of this study was to identify proteins aberrantly regulated in ASPS and to clarify their clinical significance. Protein expression profiling of tumor and nontumor tissues from 12 ASPS patients was performed by 2-D difference gel electrophoresis and mass spectrometry. We found that the expression of 145 proteins differed significantly. Among them, further investigation was focused on the SET protein, which has multifunctional roles in cancers. Immunohistochemistry confirmed overexpression of SET in all 15 ASPS cases examined. Gene silencing of SET significantly decreased cell proliferation, invasion, and migration against a background of induced apoptosis. SET is known to be an inhibitor of phosphatase 2A (PP2A), which functions as a tumor suppressor by inhibiting the signal transduction pathway and inducing apoptosis. We found that a PP2A activator, FTY720, decreased cell proliferation through apoptosis. Together, our findings may suggest the possible contribution of SET to the tumor progression and the utility of FTY720 for treatment of ASPS.

Selvarajah S, Pyne S, Chen E, et al.
High-resolution array CGH and gene expression profiling of alveolar soft part sarcoma.
Clin Cancer Res. 2014; 20(6):1521-30 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis.
EXPERIMENTAL DESIGN: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations.
RESULTS: FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation.
CONCLUSION: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS.

Ellis CL, Eble JN, Subhawong AP, et al.
Clinical heterogeneity of Xp11 translocation renal cell carcinoma: impact of fusion subtype, age, and stage.
Mod Pathol. 2014; 27(6):875-86 [PubMed] Related Publications
Xp11 translocation renal cell carcinomas harbor chromosome translocations involving the Xp11 breakpoint, resulting in gene fusions involving the TFE3 gene. The most common subtypes are the ASPSCR1-TFE3 renal cell carcinomas resulting from t(X;17)(p11;q25) translocation, and the PRCC-TFE3 renal cell carcinomas, resulting from t(X;1)(p11;q21) translocation. A formal clinical comparison of these two subtypes of Xp11 translocation renal cell carcinomas has not been performed. We report one new genetically confirmed Xp11 translocation renal cell carcinoma of each type. We also reviewed the literature for all published cases of ASPSCR1-TFE3 and PRCC-TFE3 renal cell carcinomas and contacted all corresponding authors to obtain or update the published follow-up information. Study of two new, unpublished cases, and review of the literature revealed that 8/8 patients who presented with distant metastasis had ASPSCR1-TFE3 renal cell carcinomas, and all but one of these patients either died of disease or had progressive disease. Regional lymph nodes were involved by metastasis in 24 of the 32 ASPSCR1-TFE3 cases in which nodes were resected, compared with 5 of 14 PRCC-TFE3 cases (P=0.02).; however, 11 of 13 evaluable patients with ASPSCR1-TFE3 renal cell carcinomas who presented with N1M0 disease remained disease free. Two PRCC-TFE3 renal cell carcinomas recurred late (at 20 and 30 years, respectively). In multivariate analysis, only older age or advanced stage at presentation (not fusion subtype) predicted death. In conclusion, ASPSCR1-TFE3 renal cell carcinomas are more likely to present at advanced stage (particularly node-positive disease) than are PRCC-TFE3 renal cell carcinomas. Although systemic metastases portend a grim prognosis, regional lymph node involvement does not, at least in short-term follow-up. The tendency for PRCC-TFE3 renal cell carcinomas to recur late warrants long-term follow-up.

Zadnik PL, Yurter A, DeLeon R, et al.
Alveolar soft-part sarcoma in the sacrum: a case report and review of the literature.
Skeletal Radiol. 2014; 43(1):115-20 [PubMed] Related Publications
Alveolar soft part sarcoma (ASPS) is a rare disease of the soft tissue. Although the disease is rare, it is refractory to chemotherapy and radiation. En bloc surgical resection offers the best chance of cure. In this article we report the case of a 28-year-old woman who presented with buttock and leg pain, bowel, bladder and gait impairment and a large mass in the sacrum. Following surgical excision, the lesion was proven to be ASPS. On pathology, the mass was TFE3 (transcription factor E3) positive, indicating the presence of the ASPL-TFE3 (novel gene-transcription factor) translocation. Following surgery, the patient had improvement in her pain and ambulation; however, she refused adjuvant therapy to pursue hospice care and succumbed to her disease 2 years after surgery. On a review of the literature, it was found that ASPS of the bone constitutes a rare and formidable subset of this disease. Further, metastases related to ASPS are common in the lungs, liver, brain, and lymph nodes. The degree of dissemination is a predictor of outcome, with 5-year survival of 81-88% in patients with local disease and only 20-46% in patients with metastatic disease at the time of presentation. Brain metastases at the time of presentation portend the worst prognosis.

Deshpande R, Asiedu MK, Klebig M, et al.
A comparative genomic approach for identifying synthetic lethal interactions in human cancer.
Cancer Res. 2013; 73(20):6128-36 [PubMed] Free Access to Full Article Related Publications
Synthetic lethal interactions enable a novel approach for discovering specific genetic vulnerabilities in cancer cells that can be exploited for the development of therapeutics. Despite successes in model organisms such as yeast, discovering synthetic lethal interactions on a large scale in human cells remains a significant challenge. We describe a comparative genomic strategy for identifying cancer-relevant synthetic lethal interactions whereby candidate interactions are prioritized on the basis of genetic interaction data available in yeast, followed by targeted testing of candidate interactions in human cell lines. As a proof of principle, we describe two novel synthetic lethal interactions in human cells discovered by this approach, one between the tumor suppressor gene SMARCB1 and PSMA4, and another between alveolar soft-part sarcoma-associated ASPSCR1 and PSMC2. These results suggest therapeutic targets for cancers harboring mutations in SMARCB1 or ASPSCR1 and highlight the potential of a targeted, cross-species strategy for identifying synthetic lethal interactions relevant to human cancer.

Reis H, Hager T, Wohlschlaeger J, et al.
Mammalian target of rapamycin pathway activity in alveolar soft part sarcoma.
Hum Pathol. 2013; 44(10):2266-74 [PubMed] Related Publications
Alveolar soft part sarcoma (ASPS) is a distinct type of soft tissue sarcoma holding a specific ASPL-TFE3 fusion transcript. Curative therapy is based on surgical removal, whereas lately, antiangiogenic targeted therapy regimens have proven effective. In ASPS, analysis of small series additionally display mTOR (mammalian target of rapamycin) pathway activity, thus making mTOR a possible additive target in ASPS, because it is in other tumor entities. Therefore, we systematically evaluated mTOR pathway activity in a large series of ASPS in comparison with soft tissue sarcomas of other differentiation (non-ASPS). Upstream and downstream factors of mTOR signaling and ancillary targets were analyzed in 103 cases (22 ASPS, 81 non-ASPS) by immunohistochemistry mostly using phospho-specific antibodies. TFE3 (transcription factor for immunoglobulin heavy-chain enhancer 3) translocation status was determined by FISH and RT-PCR. All ASPS were positive in TFE3 break-apart FISH and exhibited specific fusion products when RNA was available (type 1: 9x, type 2: 11x), whereas TFE3-immunoreactive non-ASPS did not. In ASPS, TFE3-, cMET-, pAKT T308- (all P < .0001), pp70S6K- (P = .002), and p4EBP1 (P = .087) expression levels were elevated, whereas pAKT S473 was decreased (P < .0001). In addition, ASPS exhibited higher TFE3-, cMET-, pAKT T308-, and pp70S6K- expression levels compared with TFE3-immunopositive non-ASPS sarcomas (all P < .001). We demonstrate elevated mTOR complex 1 (mTORC1) activity in ASPS independent of mTOR complex 2 (mTORC2) activation. mTORC1 activity seems to be related to the existence of ASPL-TFE3 fusion transcripts because TFE3-immunoreactive non-ASPS without ASPL-TFE3 fusion transcripts exhibit significantly lower mTORC1 activation status. Small molecule-based targeting of mTOR might therefore represent a potential mechanism in ASPS alone or in combination with contemporary upstream approaches.

Hodge JC, Pearce KE, Wang X, et al.
Molecular cytogenetic analysis for TFE3 rearrangement in Xp11.2 renal cell carcinoma and alveolar soft part sarcoma: validation and clinical experience with 75 cases.
Mod Pathol. 2014; 27(1):113-27 [PubMed] Related Publications
Renal cell carcinoma with TFE3 rearrangement at Xp11.2 is a distinct subtype manifesting an indolent clinical course in children, with recent reports suggesting a more aggressive entity in adults. This subtype is morphologically heterogeneous and can be misclassified as clear cell or papillary renal cell carcinoma. TFE3 is also rearranged in alveolar soft part sarcoma. To aid in diagnosis, a break-apart strategy fluorescence in situ hybridization (FISH) probe set specific for TFE3 rearrangement and a reflex dual-color, single-fusion strategy probe set involving the most common TFE3 partner gene, ASPSCR1, were validated on formalin-fixed, paraffin-embedded tissues from nine alveolar soft part sarcoma, two suspected Xp11.2 renal cell carcinoma, and nine tumors in the differential diagnosis. The impact of tissue cut artifact was reduced through inclusion of a chromosome X centromere control probe. Analysis of the UOK-109 renal carcinoma cell line confirmed the break-apart TFE3 probe set can distinguish the subtle TFE3/NONO fusion-associated inversion of chromosome X. Subsequent extensive clinical experience was gained through analysis of 75 cases with an indication of Xp11.2 renal cell carcinoma (n=54), alveolar soft part sarcoma (n=13), perivascular epithelioid cell neoplasms (n=2), chordoma (n=1), or unspecified (n=5). We observed balanced and unbalanced chromosome X;17 translocations in both Xp11.2 renal cell carcinoma and alveolar soft part sarcoma, supporting a preference but not a necessity for the translocation to be balanced in the carcinoma and unbalanced in the sarcoma. We further demonstrate the unbalanced separation is atypical, with TFE3/ASPSCR1 fusion and loss of the derivative X chromosome but also an unanticipated normal X chromosome gain in both males and females. Other diverse sex chromosome copy number combinations were observed. Our TFE3 FISH assay is a useful adjunct to morphologic analysis of such challenging cases and will be applicable to assess the growing spectrum of TFE3-rearranged tumors.

Hirobe M, Masumori N, Tanaka T, et al.
Establishment of an ASPL-TFE3 renal cell carcinoma cell line (S-TFE).
Cancer Biol Ther. 2013; 14(6):502-10 [PubMed] Free Access to Full Article Related Publications
Xp11 translocation renal cell carcinoma is a rare disease diagnosed in children and adolescents in the advanced stage with an aggressive clinical course. Various gene fusions including the transcription factor E3 (TFE3) gene located on chromosome X cause the tumor. We established an Xp11 translocation renal cell carcinoma cell line from a renal tumor in a 18-y-old Japanese female and named it "S-TFE." The cell line and its xenograft demonstrated definite gene fusion including TFE3. They showed strong nuclear staining for TFE3 in immunohistochemistry, TFE3 gene rearrangement in dual-color, break-apart FISH analysis and ASPL-TFE3 type 1 fusion transcripts detected by RT-PCR and direct DNA sequencing. Although many renal cell carcinoma cell lines have been established and investigated, only a few cell lines are recognized as Xp11.2 translocation carcinoma. S-TFE will be useful to examine the characteristics and drug susceptibility of Xp11 translocation renal cell carcinoma.

Kummar S, Allen D, Monks A, et al.
Cediranib for metastatic alveolar soft part sarcoma.
J Clin Oncol. 2013; 31(18):2296-302 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs).
PATIENTS AND METHODS: We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging.
RESULTS: Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis.
CONCLUSION: In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib.

Kobos R, Nagai M, Tsuda M, et al.
Combining integrated genomics and functional genomics to dissect the biology of a cancer-associated, aberrant transcription factor, the ASPSCR1-TFE3 fusion oncoprotein.
J Pathol. 2013; 229(5):743-54 [PubMed] Free Access to Full Article Related Publications
Oncogenic rearrangements of the TFE3 transcription factor gene are found in two distinct human cancers. These include ASPSCR1-TFE3 in all cases of alveolar soft part sarcoma (ASPS) and ASPSCR1-TFE3, PRCC-TFE3, SFPQ-TFE3 and others in a subset of paediatric and adult RCCs. Here we examined the functional properties of the ASPSCR1-TFE3 fusion oncoprotein, defined its target promoters on a genome-wide basis and performed a high-throughput RNA interference screen to identify which of its transcriptional targets contribute to cancer cell proliferation. We first confirmed that ASPSCR1-TFE3 has a predominantly nuclear localization and functions as a stronger transactivator than native TFE3. Genome-wide location analysis performed on the FU-UR-1 cell line, which expresses endogenous ASPSCR1-TFE3, identified 2193 genes bound by ASPSCR1-TFE3. Integration of these data with expression profiles of ASPS tumour samples and inducible cell lines expressing ASPSCR1-TFE3 defined a subset of 332 genes as putative up-regulated direct targets of ASPSCR1-TFE3, including MET (a previously known target gene) and 64 genes as down-regulated targets of ASPSCR1-TFE3. As validation of this approach to identify genuine ASPSCR1-TFE3 target genes, two up-regulated genes bound by ASPSCR1-TFE3, CYP17A1 and UPP1, were shown by multiple lines of evidence to be direct, endogenous targets of transactivation by ASPSCR1-TFE3. As the results indicated that ASPSCR1-TFE3 functions predominantly as a strong transcriptional activator, we hypothesized that a subset of its up-regulated direct targets mediate its oncogenic properties. We therefore chose 130 of these up-regulated direct target genes to study in high-throughput RNAi screens, using FU-UR-1 cells. In addition to MET, we provide evidence that 11 other ASPSCR1-TFE3 target genes contribute to the growth of ASPSCR1-TFE3-positive cells. Our data suggest new therapeutic possibilities for cancers driven by TFE3 fusions. More generally, this work establishes a combined integrated genomics/functional genomics strategy to dissect the biology of oncogenic, chimeric transcription factors.

Covell DG, Wallqvist A, Kenney S, Vistica DT
Bioinformatic analysis of patient-derived ASPS gene expressions and ASPL-TFE3 fusion transcript levels identify potential therapeutic targets.
PLoS One. 2012; 7(11):e48023 [PubMed] Free Access to Full Article Related Publications
Gene expression data, collected from ASPS tumors of seven different patients and from one immortalized ASPS cell line (ASPS-1), was analyzed jointly with patient ASPL-TFE3 (t(X;17)(p11;q25)) fusion transcript data to identify disease-specific pathways and their component genes. Data analysis of the pooled patient and ASPS-1 gene expression data, using conventional clustering methods, revealed a relatively small set of pathways and genes characterizing the biology of ASPS. These results could be largely recapitulated using only the gene expression data collected from patient tumor samples. The concordance between expression measures derived from ASPS-1 and both pooled and individual patient tumor data provided a rationale for extending the analysis to include patient ASPL-TFE3 fusion transcript data. A novel linear model was exploited to link gene expressions to fusion transcript data and used to identify a small set of ASPS-specific pathways and their gene expression. Cellular pathways that appear aberrantly regulated in response to the t(X;17)(p11;q25) translocation include the cell cycle and cell adhesion. The identification of pathways and gene subsets characteristic of ASPS support current therapeutic strategies that target the FLT1 and MET, while also proposing additional targeting of genes found in pathways involved in the cell cycle (CHK1), cell adhesion (ARHGD1A), cell division (CDC6), control of meiosis (RAD51L3) and mitosis (BIRC5), and chemokine-related protein tyrosine kinase activity (CCL4).

Ohe C, Kuroda N, Hes O, et al.
A renal epithelioid angiomyolipoma/perivascular epithelioid cell tumor with TFE3 gene break visualized by FISH.
Med Mol Morphol. 2012; 45(4):234-7 [PubMed] Related Publications
We present a case of renal epithelioid angiomyolipoma (eAML)/perivascular epithelioid cell tumor (PEComa) with a TFE3 gene break visible by fluorescence in situ hybridization (FISH). Histologically, the tumor was composed of mainly epithelioid cells forming solid arrangements with small foci of spindle cells. In a small portion of the tumor, neoplastic cells displayed nuclear pleomorphism, such as polygonal and enlarged vesicular nuclei with prominent nucleoli. Marked vascularity was noticeable in the background, and perivascular hyaline sclerosis was also seen. Immunohistochemically, neoplastic cells were diffusely positive for α-smooth muscle actin and melanosome in the cytoplasm. Nuclei of many neoplastic cells were positive for TFE3. FISH analysis of the TFE3 gene break using the Poseidon TFE3 (Xp11) Break probe revealed positive results. Reverse transcriptase-polymerase chain reactions (RT-PCR) for ASPL/TFE3, PRCC/TFE3, CLTC/TFE3, PSF/TFE3, and NonO/TFE3 gene fusions all revealed negative results. This is the first reported case of renal eAML/PEComa with a TFE3 gene break, and it has unique histological findings as compared to previously reported TFE3 gene fusion-positive PEComas. Pathologists should recognize that PEComa with TFE3 gene fusion can arise even in the kidney.

Wagstaff L, Kolahgar G, Piddini E
Competitive cell interactions in cancer: a cellular tug of war.
Trends Cell Biol. 2013; 23(4):160-7 [PubMed] Related Publications
Within tissues, cells sense differences in fitness levels and this can lead to fitter cells eliminating less fit, albeit viable, cells via competitive cell interactions. The involvement of several cancer-related genes in this phenomenon has drawn attention to a potential connection between competitive cell interactions and cancer. Indeed, initial studies found that tumor-promoting genes can turn cells into 'supercompetitors', able to kill normal cells around them. However, more recently it has been observed that cells harboring certain cancer-promoting mutations can be eliminated by surrounding normal cells, suggesting that competitive cell interactions could also have a tumor-suppressive role. These findings suggest a new view whereby tumor and host cells engage in a bidirectional tug of war, the outcome of which may have a profound impact on disease progression.

Wagner AJ, Goldberg JM, Dubois SG, et al.
Tivantinib (ARQ 197), a selective inhibitor of MET, in patients with microphthalmia transcription factor-associated tumors: results of a multicenter phase 2 trial.
Cancer. 2012; 118(23):5894-902 [PubMed] Related Publications
BACKGROUND: Microphthalmia transcription factor (MITF)-associated (MiT) tumors are a family of rare malignancies, including alveolar soft part sarcoma (ASPS), clear cell sarcoma (CCS), and translocation-associated renal cell carcinoma (tRCC) that have dysregulated expression of oncogenic MITF family proteins. The MET receptor tyrosine kinase gene is transcriptionally activated by MITF family proteins, making MET a potential therapeutic target for MiT tumors. This study assessed the activity of tivantinib (ARQ 197), a selective MET inhibitor, in patients with MiT-associated tumors.
METHODS: This multicenter, single-arm, phase 2 trial enrolled patients with advanced MiT tumors. Patients initially received tivantinib 120 mg orally twice daily, then 360 mg twice daily per protocol amendment. The primary endpoint was overall response rate. Secondary endpoints included safety, progression-free survival, pharmacokinetics, and correlative studies.
RESULTS: A total of 47 patients (median age, 25 years; range, 11-73 years) with ASPS (n = 27), CCS (n = 11), tRCC (n = 6), or other tumor types (n = 3) were enrolled. Common grade 3/4 drug-related adverse events included anemia (4%) and neutropenia (4%). Three patients (6.4%) experienced 4 treatment-related serious adverse events (grade 3 febrile neutropenia, thrombocytopenia, and deep vein thrombosis, and grade 4 thrombocytopenia). Best response was partial response in 1 CCS patient (2%) and stable disease in 28 patients (60%). Median progression-free survival was 3.6 months (overall), 5.5 months (ASPS), and 1.9 months (CCS and tRCC). Baseline MET expression was strongly or focally positive in tumor samples from 14 of 19 patients (74%).
CONCLUSIONS: Tivantinib was safe and tolerable in patients with MiT tumors, but antitumor activity was modest.

Klatte T, Streubel B, Wrba F, et al.
Renal cell carcinoma associated with transcription factor E3 expression and Xp11.2 translocation: incidence, characteristics, and prognosis.
Am J Clin Pathol. 2012; 137(5):761-8 [PubMed] Related Publications
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.

Tug E, Balaban YH, Sahin EK
Mapping of microsatellite instability in endoscopic normal colon.
Genet Test Mol Biomarkers. 2012; 16(5):388-95 [PubMed] Related Publications
Genomic instability in colorectal cancer (CRC) occurs as either microsatellite instability (MSI) or chromosomal instability. The present study was aimed at examining the MSI for the MLH1 and MSH2 genes in normal colon and polyps, if detected. Four segments of the colon were sampled in 102 subjects during colonoscopy. DNA samples were analyzed for the MSI status according to the Bethesda consensus panel. Family history of any type of cancer or for colon cancer was present in 44.8% and 9.4% of the individuals, respectively. Forty-eight percent of individuals were microsatellite stable for all five markers at all locations, 20% had low MSI status (MSI-L), and 32% had high MSI status (MSI-H). The frequencies of MSI markers differed significantly from each other (p=0.003). The most frequent positive marker was D17S250. This is the first study which revealed that MSI is present in endoscopically normal-looking colon of normal individuals and, more frequently, in individuals with family histories of CRC. The detection of very early-stage CRC is possible by MSI analysis of DNA mismatch repair genes in colon tissues. This study has revealed crucial information for the use of molecular tests in CRC screening, such as high frequencies of MSI in endoscopically normal colon, which might cause false positivity.

Kuroda N, Mikami S, Pan CC, et al.
Review of renal carcinoma associated with Xp11.2 translocations/TFE3 gene fusions with focus on pathobiological aspect.
Histol Histopathol. 2012; 27(2):133-40 [PubMed] Related Publications
The concept of Xp11.2 renal cell carcinoma (RCC) was recently established as a tumor affecting 15% of RCC patients <45 years. Many patients present with advanced stage with frequent lymph node metastases. Histologically, Xp11.2 RCC is characterized by mixed papillary nested/alveolar growth pattern and tumor cells with clear and/or eosinophilic, voluminous cytoplasm. Neoplastic cells show intense nuclear immunoreactivity to TFE3, while focal immunostaining for melanocytic markers, including melanosome-associated antigen or Melan A in some cases, are also noted. Alpha smooth muscle actin and TFEB are consistently negative. Ultrastructurally, the ASPL-TFE3 RCC variant contains rhomboid crystals in the cytoplasm, similar to that observed in alveolar soft part sarcoma. The fusion of the TFE3 gene with several different genes, including ASPL(17q25), PRCC(1q21), PSF(1q34), NonO (Xq12) and CLTC (17q23) have been identified to date. The behavior of Xp11.2 RCC in children and young adults is considered as indolent even when diagnosed at advanced stage, including lymph node metastasis. However, Xp11.2 RCC in older patients behaves in a more aggressive fashion. Therapy includes nephrectomy with extended lymphadenectomy. There may be a role for new protease inhibitors in advanced inoperable disease. Further research is required to correlate clinical behavior with the expanding genetic spectrum of this tumor, and to establish standard therapy protocols for primary and metastatic lesions.

Tsuji K, Ishikawa Y, Imamura T
Technique for differentiating alveolar soft part sarcoma from other tumors in paraffin-embedded tissue: comparison of immunohistochemistry for TFE3 and CD147 and of reverse transcription polymerase chain reaction for ASPSCR1-TFE3 fusion transcript.
Hum Pathol. 2012; 43(3):356-63 [PubMed] Related Publications
The diagnosis of alveolar soft part sarcoma is commonly based on characteristic histology and distinctive periodic acid-Schiff-positive crystals; however, the characteristic crystals may not always be observed, rendering the diagnosis difficult. Three important characteristics of alveolar soft part sarcoma, the presence of ASPSCR1-TFE3 fusion transcript, nuclear immunoreactivity for TFE3, and immunoreactivity for monocarboxylate transporter 1 and CD147, have recently been reported. To identify the best marker for alveolar soft part sarcoma in formalin-fixed, paraffin-embedded tissues, we evaluated the sensitivity and specificity of the detection of the ASPSCR1-TFE3 fusion transcript along with the immunoreactivity for TFE3 and CD147 in 24 alveolar soft part sarcomas and 23 non-alveolar soft part sarcoma tumors, including 5 granular cell tumors, 5 paragangliomas, 3 clear cell sarcomas, and 10 clear cell renal cell carcinomas. The ASPSCR1-TFE3 fusion transcript was detected in 24 of 24 alveolar soft part sarcomas (7 type 1, 17 type 2), and TFE3 immunoreactivity was observed in 22 of 24 alveolar soft part sarcomas. In non-alveolar soft part sarcoma tumors, the ASPSCR1-TFE3 fusion transcript was not detected; however, the TFE3 immunoreactivity was observed in 2 of 5 granular cell tumors. CD147 immunoreactivity was demonstrated in 20 of 24 alveolar soft part sarcomas, 3 of 5 granular cell tumors, and 8 of 10 clear cell renal cell carcinomas. Our results demonstrate that the most sensitive marker of alveolar soft part sarcoma was the presence of the ASPSCR1-TFE3 fusion transcript. Thus, detection of the ASPSCR1-TFE3 fusion transcript was considered applicable for formalin-fixed, paraffin-embedded tissues with superior sensitivity as compared with TFE3 immunohistochemical staining. In alveolar soft part sarcomas with unusual locations or histology, we consider that the detection of the ASPSCR1-TFE3 fusion transcript would be the highly effective diagnostic technique.

Martignoni G, Gobbo S, Camparo P, et al.
Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions.
Mod Pathol. 2011; 24(10):1313-9 [PubMed] Related Publications
Cathepsin K is a protease whose expression is driven by microphthalmia transcription factor (MITF) in osteoclasts. TFE3 and TFEB are members of the same transcription factor subfamily as MITF and all three have overlapping transcriptional targets. We have shown that all t(6;11) renal cell carcinomas, which harbor an Alpha-TFEB gene fusion, as well as a subset of the Xp11 translocation renal carcinomas, which harbor various TFE3 gene fusions, express cathepsin K, while no other common renal carcinoma does. We have hypothesized that overexpression of TFEB or certain TFE3 fusion proteins function like MITF in these neoplasms, and thus activate cathepsin K expression. However, the expression of cathepsin K in specific genetic subtypes of Xp11 translocation carcinomas, as well as alveolar soft part sarcoma, which harbors the same ASPSCR1-TFE3 gene fusion as some Xp11 translocation carcinomas, has not been addressed. We performed immunohistochemistry for cathepsin K on 14 genetically confirmed t(X;1)(p11;q21) carcinomas, harboring the PRCC-TFE3 gene fusion; eight genetically confirmed t(X;17)(p11;q25) carcinomas, harboring the ASPSCR1-TFE3 gene fusion; and 18 alveolar soft part sarcomas (12 genetically confirmed), harboring the identical ASPSCR1-TFE3 gene fusion. All 18 alveolar soft part sarcomas expressed cathepsin K. In contrast, all eight ASPSCR1-TFE3 carcinomas were completely negative for cathepsin K. However, 12 of 14 PRCC-TFE3 carcinomas expressed cathepsin K. Expression of cathepsin K distinguishes alveolar soft part sarcoma from the ASPSCR1-TFE3 carcinoma, harboring the same gene fusion. The latter can be useful diagnostically, especially when alveolar soft part sarcoma presents in an unusual site (such as bone) or with clear cell morphology, which raises the differential diagnosis of metastatic ASPSCR1-TFE3 renal cell carcinoma. The difference in expression of cathepsin K between the PRCC-TFE3 and ASPSCR1-TFE3 carcinomas, together with the observed clinical differences between these subtypes of Xp11 translocation carcinomas, suggests the possibility of functional differences between these two related fusion proteins.

Kenney S, Vistica DT, Stockwin LH, et al.
ASPS-1, a novel cell line manifesting key features of alveolar soft part sarcoma.
J Pediatr Hematol Oncol. 2011; 33(5):360-8 [PubMed] Related Publications
In vitro growth of alveolar soft part sarcoma (ASPS) and establishment of an ASPS cell line, ASPS-1, are described in this study. Using a recently developed xenograft model of ASPS derived from a lymph node metastasis, organoid nests consisting of 15 to 25 ASPS cells were isolated from ASPS xenograft tumors by capture on 70 μm filters and plated in vitro. After attachment to the substratum, these nests deposited small aggregates of ASPS cells. These cells grew slowly and were expanded over a period of 3 years and have maintained characteristics consistent with those of both the original ASPS tumor from the patient and the xenograft tumor including (1) presence of the alveolar soft part locus-transcription factor E3 type 1 fusion transcript and nuclear expression of the alveolar soft part locus-transcription factor E3 type 1 fusion protein; (2) maintenance of the t(X;17)(p11;q25) translocation characteristic of ASPS; and (3) expression of upregulated ASPS transcripts involved in angiogenesis (ANGPTL2, HIF-1-α, MDK, c-MET, VEGF, and TIMP-2), cell proliferation (PRL, PCSK1), metastasis (ADAM9), as well as the transcription factor BHLHB3 and the muscle-specific transcripts TRIM63 and ITGβ1BP3. This ASPS cell line forms colonies in soft agar and retains the ability to produce highly vascularized ASPS tumors in NOD.SCID/NCr mice. Immunohistochemistry of selected ASPS markers on these tumors indicated similarity to those of the original patient tumor as well as to the xenografted ASPS tumor. We anticipate that this ASPS cell line will accelerate investigations into the biology of ASPS including identification of new therapeutic approaches for treatment of this slow growing soft tissue sarcoma.

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