Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma

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Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma

Identity

Other names Renal cell carcinoma with CLTC-TFE3 gene fusion

Classification

This renal cell carcinoma, of which there is only a single reported case, belongs to the family of Xp11 translocation renal carcinomas.

Clinics and Pathology

Etiology Unclear

Epidemiology Single case report in a 14 year old male

Pathology The tumor was bounded by a calcified fibrous pseudocapsule. The tumor had predominantly a solid, compact nested pattern, as islands of tumor cells were demarcated by fibrovascular septa. More dyscohesive areas yielded a papillary architecture. Focal calcifications, some in the form of psammoma bodies, were frequent, often associated with hyaline nodules. Tumor cells were polygonal with well-demarcated, predominantly clear, voluminous cytoplasm. However, there were scattered areas in which the cells were smaller and others where they demonstrated densely eosinophilic cytoplasm; the latter areas had a nested growth pattern and foci of central necrosis, somewhat reminiscent of hepatocellular carcinoma. Mitoses were sparse.
Immunohistochemical (IHC) analysis showed strong and diffuse nuclear labeling with a polyclonal antibody to the TFE3 C-terminal portion , as seen in other tumors associated with TFE3 gene fusions. Since native TFE3 protein is not detectable in non-neoplastic cells by the same assay, this finding is consistent with constitutive expression of a nuclear fusion protein containing the TFE3 C-terminal portion, such as the predicted CLTC-TFE3 protein. Like most conventional (clear cell) and papillary RCCs, the tumor contained tumor cells were strongly and diffusely immunoreactive for CD10, showing strong cytoplasmic staining with membranous accentuation. However, unlike most typical adult RCCs, IHC with all cytokeratin antibodies (Cam5.2, AE1/3, Cytokeratin 7) and the ³RCC² monoclonal antibody yielded negative reactions, though tumor cells did label in one isolated area for Epithelial Membrane Antigen (EMA). Underexpression of common epithelial proteins is a typical feature of Xp11.2-translocation carcinomas. Surprisingly, the tumor was focally immunoreactive for the melanocytic proteins Melan-A and HMB45 but IHC assays for MiTF and S100 protein were negative. While unusual, the immunoreactivity for melanocytic markers can be seen in Xp11 translocation carcinomas.

Treatment Nephrectomy

Prognosis Unclear

Genes involved and Proteins

Note The t(X;17)(p11.2;q23) results in a CLTC-TFE3 gene fusion.

Gene Name TFE3

Location Xp11.2

Dna / Rna The TFE3 gene includes a 5¹ untranslated region, 8 exons, and a 3¹ untranslated region.

Protein TFE3 is a transcription factor with a basic helix-loop-helix DNA binding domain and a leucine zipper dimerization domain. TFE3 contains a nuclear localization signal, encoded at the junction of exons 5 and 6, which is retained within all known TFE3 fusion proteins. TFE3 protein is 575 amino acids, and is ubiquitously expressed.
TFE3, TFEB, TFEC and Mitf comprise the members of the microphthalmia transcription factor subfamily, which have homologous DNA binding domains and can bind to a common DNA sequence. These four transcription factors may homo- or heterodimerize to bind DNA, and they may have functional overlap.

Gene Name CLTC

Location 17q23

Note Clathrin is the major protein constituent of the coat that surrounds organelles (cytoplasmic vesicles) to mediate selective protein transport. Clathrin coats are involved in receptor-mediated endocytosis and intracellular trafficking and recycling of receptors, which accounts for its characteristic punctate cytoplasmic and perinuclear cellular distribution. Structurally, clathrin is a triskelion (three-legged) shaped protein complex that is composed of a trimer of heavy chains (CLTC) each bound to a single light chain. CLTC is a 1675 amino acid residue protein encoded by a gene consisting of 32 exons. Its known domains include a N-terminal globular domain (residues 1-494) that interacts with adaptor proteins (AP-1, AP-2, b-arrestin), a light chain-binding region (residues 1074-1552), and a trimerization domain (residues 1550-1600) near the C-terminus.

Result of the chromosomal anomaly

Fusion Protein
Description In the CLTC-TFE3 fusion, the fusion point on CLTC is at amino acid 932 (corresponding to the end of exon 17), thereby excluding the CLTC trimerization domain from the predicted fusion protein. As in other TFE3 gene fusions, the nuclear localization and DNA binding domains of TFE3 are retained in CLTC-TFE3. Based on these features and existing data on other TFE3 fusion proteins, CLTC-TFE3 may act as an aberrant transcription factor, with the CLTC promoter driving constitutive expression.

Bibliography

Distinctive neoplasms characterized by specific chromosome translocations comprise a significant proportion of paediatric renal cell carcinomas.

Argani P, Ladanyi M.

Pathology 2003; 35: 492-498.

PMID 14660099

Aberrant nuclear immunoreactivity for TFE3 in neoplasms with TFE3 gene fusions: a sensitive and specific immunohistochemical assay.

Argani P, Lal P, Hutchinson B, Lui MY, Reuter VE, Ladanyi M.

Am J Surg Pathol 2003; 27: 750-761.

PMID 12766578

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

Argani P, Lui MY, Couturier J, Bouview R, Fournet JC, Ladanyi M.

Oncogene 2003; 22: 5374-5378.

PMID 12917640

REVIEW articles automatic search in PubMed

Last year publications automatic search in PubMed

Contributor(s)

Written 04-2005 Pedram Argani, Marc Ladanyi

Citation

This paper should be referenced as such :
Argani P, Ladanyi M . Kidney: t(X;17)(p11.2;q23) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. April 2005 .
URL : http://AtlasGeneticsOncology.org/Tumors/RenalCellt0X17ID5035.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Thu Apr 17 14:14:48 2008

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Etiology	Unclear
Epidemiology	Single case report in a 14 year old male
Pathology	The tumor was bounded by a calcified fibrous pseudocapsule. The tumor had predominantly a solid, compact nested pattern, as islands of tumor cells were demarcated by fibrovascular septa. More dyscohesive areas yielded a papillary architecture. Focal calcifications, some in the form of psammoma bodies, were frequent, often associated with hyaline nodules. Tumor cells were polygonal with well-demarcated, predominantly clear, voluminous cytoplasm. However, there were scattered areas in which the cells were smaller and others where they demonstrated densely eosinophilic cytoplasm; the latter areas had a nested growth pattern and foci of central necrosis, somewhat reminiscent of hepatocellular carcinoma. Mitoses were sparse. Immunohistochemical (IHC) analysis showed strong and diffuse nuclear labeling with a polyclonal antibody to the TFE3 C-terminal portion , as seen in other tumors associated with TFE3 gene fusions. Since native TFE3 protein is not detectable in non-neoplastic cells by the same assay, this finding is consistent with constitutive expression of a nuclear fusion protein containing the TFE3 C-terminal portion, such as the predicted CLTC-TFE3 protein. Like most conventional (clear cell) and papillary RCCs, the tumor contained tumor cells were strongly and diffusely immunoreactive for CD10, showing strong cytoplasmic staining with membranous accentuation. However, unlike most typical adult RCCs, IHC with all cytokeratin antibodies (Cam5.2, AE1/3, Cytokeratin 7) and the ³RCC² monoclonal antibody yielded negative reactions, though tumor cells did label in one isolated area for Epithelial Membrane Antigen (EMA). Underexpression of common epithelial proteins is a typical feature of Xp11.2-translocation carcinomas. Surprisingly, the tumor was focally immunoreactive for the melanocytic proteins Melan-A and HMB45 but IHC assays for MiTF and S100 protein were negative. While unusual, the immunoreactivity for melanocytic markers can be seen in Xp11 translocation carcinomas.


Treatment	Nephrectomy
Prognosis	Unclear

Gene Name	TFE3
Location	Xp11.2
Dna / Rna	The TFE3 gene includes a 5¹ untranslated region, 8 exons, and a 3¹ untranslated region.
Protein	TFE3 is a transcription factor with a basic helix-loop-helix DNA binding domain and a leucine zipper dimerization domain. TFE3 contains a nuclear localization signal, encoded at the junction of exons 5 and 6, which is retained within all known TFE3 fusion proteins. TFE3 protein is 575 amino acids, and is ubiquitously expressed. TFE3, TFEB, TFEC and Mitf comprise the members of the microphthalmia transcription factor subfamily, which have homologous DNA binding domains and can bind to a common DNA sequence. These four transcription factors may homo- or heterodimerize to bind DNA, and they may have functional overlap.

Gene Name	CLTC
Location	17q23
Note	Clathrin is the major protein constituent of the coat that surrounds organelles (cytoplasmic vesicles) to mediate selective protein transport. Clathrin coats are involved in receptor-mediated endocytosis and intracellular trafficking and recycling of receptors, which accounts for its characteristic punctate cytoplasmic and perinuclear cellular distribution. Structurally, clathrin is a triskelion (three-legged) shaped protein complex that is composed of a trimer of heavy chains (CLTC) each bound to a single light chain. CLTC is a 1675 amino acid residue protein encoded by a gene consisting of 32 exons. Its known domains include a N-terminal globular domain (residues 1-494) that interacts with adaptor proteins (AP-1, AP-2, b-arrestin), a light chain-binding region (residues 1074-1552), and a trimerization domain (residues 1550-1600) near the C-terminus.

Fusion Protein
Description	In the CLTC-TFE3 fusion, the fusion point on CLTC is at amino acid 932 (corresponding to the end of exon 17), thereby excluding the CLTC trimerization domain from the predicted fusion protein. As in other TFE3 gene fusions, the nuclear localization and DNA binding domains of TFE3 are retained in CLTC-TFE3. Based on these features and existing data on other TFE3 fusion proteins, CLTC-TFE3 may act as an aberrant transcription factor, with the CLTC promoter driving constitutive expression.

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed