A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23)

Argani, Pedram; Lui, Man Yee; Couturier, Jérôme; Bouvier, Raymonde; Fournet, J; Ladanyi, Marc

doi:10.1038/sj.onc.1206686

Cited by 237 publications

(165 citation statements)

References 27 publications

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“…The expression of cathepsin K in other rarer subtypes of Xp11 translocation renal cell carcinomas remains to be determined. In limited material we have found diffuse cathepsin K labeling in one PSF-TFE3 renal cell carcinoma but no labeling in a CLTC-TFE3 renal cell carcinoma, 27 suggesting that these rarer subtypes also harbor subtle biologic differences. 10 In summary, we demonstrate here the differential expression of cathepsin K among neoplasms harboring TFE3 gene fusions.…”

Section: Discussionmentioning

confidence: 72%

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

et al. 2011

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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.

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Section: Discussionmentioning

confidence: 72%

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

et al. 2011

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“…For example, CLTC in KIRC, which is contained in CGC and ranked 11 with low mutated frequency 1.68% in DriverFinder, encodes a major subunit of clathrin and is a fusion partner of TFE3. And CLTC-TFE3 is the fifth gene fusion involving TFE3 in pediatric renal cell carcinomas [44]. Another example is AKT1 (0.69% of cases) in THCA, which is identified by DriverFinder (ranked 30) and contained in CGC; it is a serine/threonine protein kinase and its downstream proteins have been reported to be frequently activated in human cancers [45].…”

Section: Discovering Rare Driver Genesmentioning

confidence: 99%

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Wei

Zhang

et al. 2017

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Integration of multi-omics data of cancer can help people to explore cancers comprehensively. However, with a large volume of different omics and functional data being generated, there is a major challenge to distinguish functional driver genes from a sea of inconsequential passenger genes that accrue stochastically but do not contribute to cancer development. In this paper, we present a gene length-based network method, named DriverFinder, to identify driver genes by integrating somatic mutations, copy number variations, gene-gene interaction network, tumor expression, and normal expression data. To illustrate the performance of DriverFinder, it is applied to four cancer types from The Cancer Genome Atlas including breast cancer, head and neck squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Compared with some conventional methods, the results demonstrate that the proposed method is effective. Moreover, it can decrease the influence of gene length in identifying driver genes and identify some rare mutated driver genes.

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“…2 At present, five different translocations involving the Xp11.2 chromosomal region have been characterised, resulting in the fusion of the TFE3 (transcription factor binding to IGHM enhancer 3) to PRCC (t(X;1)(p11;q21)), PSF (t(X;1) (p11;p34)), NONO (inv(X)(p11;q12)), ASPL (t(X;17)(p11;q25)) or CLTC (t(X;17)(p11;q23)). [3][4][5][6] In addition, another, at present unknown fusion partner of the TFE3 has recently been located on chromosome 19q13. 1.…”

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Molecular heterogeneity of TFE3 activation in renal cell carcinomas

et al. 2012

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Renal cell carcinomas associated with Xp11.2 translocations have recently been identified as a distinct biological entity. The translocation results in the fusion of the transcription factor TFE3 to one of several different fusion partners including PRCC, PSF, NONO, ASPL or CTLC with consecutive overexpression of the chimeric protein. As the true frequency of these neoplasms as well as the biological properties of TFE3 activation in renal cell carcinomas are largely unknown, we have examined TFE3 expression as well as the underlying genetic alterations in a large, hospital-based series of renal cell carcinomas with long-term follow-up information. Out of a total of 876 tumours, TFE3 translocations were detected in five cases (0.6%). Three additional cases were identified in a second series of cases comprising of renal cell carcinomas developing in patients before the age of 50. However, using immunohistochemistry, 9% of all renal cell carcinomas showed some degree of TFE3 reactivity. Interestingly, these cases were associated with high nuclear grade, greater tumour extent and metastatic disease as well as an unfavourable patient outcome on uni-and multivariate analysis. Fluorescence in situ hybridisation (FISH) revealed TFE3 amplifications as an additional, novel mechanism leading to increased TFE3 expression levels. In conclusion, our data show that Xp11 translocation renal cell carcinomas are uncommon tumours accounting for o1% of adult renal cell carcinomas and that the diagnosis of Xp11 translocation renal cell carcinomas needs to be verified using molecular techniques. In turn, TFE3 overexpressing tumours show an aggressive behaviour and Xp11 translocation is only one of several possible underlying genomic alterations.

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A novel CLTC-TFE3 gene fusion in pediatric renal adenocarcinoma with t(X;17)(p11.2;q23)

Cited by 237 publications

References 27 publications

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

Differential expression of cathepsin K in neoplasms harboring TFE3 gene fusions

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Molecular heterogeneity of TFE3 activation in renal cell carcinomas

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