Kidney: t(6;11)(p21;q12) in renal cell carcinoma

Atlas of Genetics and Cytogenetics in Oncology and Haematology

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 NA

Kidney: t(6;11)(p21;q12) in renal cell carcinoma

Identity

Other names Alpha-TFEB renal cell carcinoma
Note A distinctive renal neoplasm with epithelioid morphology, basement membrane production focal HMB45 immunoreactivity.

Classification

This is a recently described, novel type of renal cell carcinoma, which is most likely related to the recently-described and recognized Xp11 renal translocation carcinomas.

Clinics and Pathology

Etiology Not clear, but two of 12 confirmed cases have occurred in children who were exposed to prior cytotoxic chemotherapy, raising the possibility that this tumor may be induced by chemotherapy.

Epidemiology There are 12 reported cases, 3 in males and 9 in females. The median age is 18 years (range: 6-53 years).

Pathology On microscopic examination, these neoplasms feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Papillary architecture may be seen. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini. Mitoses are rare and necrosis is usually absent. The cases examined have generally been negative for cytokeratins by immunohistochemistry, but all have labeled at least focally for HMB45 and Melan A. We have recently found that the t(6;11) renal carcinomas demonstrate specific nuclear labeling for TFEB protein by IHC while other neoplasms and normal tissues do not. Hence, nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this renal neoplasm with a TFEB gene fusion.

Treatment Nephrectomy

Prognosis Unclear at the current time. One case has metastasized and killed the patient, proving that these are malignant neoplasms.

Genes involved and Proteins

Gene Name TFEB

Location 6p21

Dna / Rna TFEB has 10 exons, with the ATG protein initiation codon located within exon 3.

Protein TFEB is a transcription factor with a basic helix-loop-helix DNA binding domain, a leucine zipper dimerization domain18, and a nuclear localization signal, thought to be located C-terminal to the helix-loop-helix domain. TFEB is ubiquitously expressed.
TFEB, TFE3, 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 Alpha

Location 11q12

Dna / Rna Alpha is an intronless, untranslated gene of unknown function.

Result of the chromosomal anomaly

Hybrid Gene
Description The breakpoint on TFEB is within its second intron, just upstream of the TFEB initiation ATG codon, which results in retention of the entire TFEB coding region in the fusion gene. Although the Alpha promoter drives expression of the fusion gene, the Alpha gene does not contribute to the open reading frame. Therefore, the consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. The TFEB-Alpha fusion gene is also expressed.

Detection RT-PCR is the standard molecular approach for detection of most translocation-associated gene fusions. This is because, in most leukemia and sarcoma translocations, genomic breakpoints are variably positioned within large introns, but the splicing of the transcripts encoded by fusion genes typically results in very consistent fusion points that can be tightly bracketed by appropriate primers to generate relatively small RT-PCR products (e.g. 100-300 bp).
In the t(6;11)(p21;q12), the lack of splicing between Alpha and TFEB results in a different and unique fusion transcript in each case that can vary considerably in size (over 1 kb) from case to case. Since RNAs extracted from clinical samples are usually partially degraded, amplification of targets in this size range is much more inefficient and the risk of false-negatives correspondingly increases. The Alpha fusion points in 7 fully characterized tumors were scattered over 1.2 kb. Because there are likely no functional consequences to different fusion points in Alpha (since it does not encode a native protein or a fusion protein with TFEB), additional Alpha fusion points outside of this breakpoint cluster region may well be found in the future. The fusion points in TFEB appear more tightly clustered; so far, all have been located in a 167 bp region near the 3¹end of intron 2. Based on the sizes of these two breakpoint cluster regions, RT-PCR product sizes using a primer at the 5¹ end of Alpha in combination with a reverse primer in exon 3 of TFEB could range in size to over 1.5 kb. This is a technical drawback for molecular diagnosis that could be addressed by using several assays with different Alpha primers scattered from the 5¹ to the 3¹ end of the gene. However the unique features of the Alpha gene as a translocation partner should result in a lack of splicing across the intron rearranged by the translocation. Indeed, this seems to be the case, since in all three cases with data on both the genomic junction sequence and the fusion transcript, the sequences have been identical. This indicates that the DNA PCR and RT-PCR products will be identical if a reverse primer that binds to TFE3 exon 3 is used. Because it is easier to isolate and amplify 1 to 1.5 kb target DNAs from clinical tumor samples than target RNAs of the same size (given the greater lability of RNA), detecting this fusion by long range DNA PCR may be a useful alternative for molecular diagnosis.

Fusion Protein
Note The Alpha-TFEB gene fusion results in dysregulated expression of native TFEB protein.

Expression Localisation TFEB protein that is overexpressed as a result of the Alpha-TFEB gene fusion localizes to the nucleus as determined by immunohistochemistry. While it is ubiquitously expressed, native TFEB in cells without this translocation is not detectable by this assay.

Bibliography

Two cases of renal cell carcinoma, clear cell type, revealing a t(6;11)(p21;q13).

Dijkhuizen T, van den Berg E, Storkel S, van Kessel AG, Janssen B, de Jong B

Cancer Genet Cytogenet. 1996 ; 91 : page 141.

A distinctive pediatric renal neoplasm characterized by epithelioid morphology, basement membrane production, focal HMB45 immunoreactivity, and t(6;11)(p21.1;q12) chromosome translocation.

Argani P, Hawkins A, Griffin CA, Goldstein JD, Haas M, Beckwith JB, Mankinen CB, Perlman EJ

The American journal of pathology. 2001 ; 158 (6) : 2089-2096.

PMID 11395386

Distinctive chromosomal translocations in pediatric renal cell carcinoma.

Yeh Y, Vargas S, Fletcher JA, Perez Atayde AR

Mod Pathol. 2002 ; 15 : page 7.

Renal carcinomas associated with Xp11 translocations/TFE3 gene fusions.

Argani P, Ladanyi M

In Eble JN, Sauter G, Epstein J, Sesterhenn I, editors..

Cloning of an Alpha-TFEB fusion in renal tumors harboring the t(6;11)(p21;q13) chromosome translocation.

Davis IJ, Hsi BL, Arroyo JD, Vargas SO, Yeh YA, Motyckova G, Valencia P, Perez-Atayde AR, Argani P, Ladanyi M, Fletcher JA, Fisher DE

Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (10) : 6051-6056.

PMID 12719541

Upregulation of the transcription factor TFEB in t(6;11)(p21;q13)-positive renal cell carcinomas due to promoter substitution.

Kuiper RP, Schepens M, Thijssen J, van Asseldonk M, van den Berg E, Bridge J, Schuuring E, Schoenmakers EF, van Kessel AG

Human molecular genetics. 2003 ; 12 (14) : 1661-1669.

PMID 12837690

Translocation carcinomas of the kidney as chemotherapy-induced secondary malignancies?

Argani P, LaˆÉ¬© M, Ballard ET, Rodriguez M, Hutchinson B, Amin M, Manivel C, Reuter VE, Ladanyi M

Mod Pathol. 2005 ; 18 : page 303.

Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.

Argani P, Laˆ© M, Hutchinson B, Reuter VE, Collins MH, Perentesis J, Tomaszewski JE, Brooks JS, Acs G, Bridge JA, Vargas SO, Davis IJ, Fisher DE, Ladanyi M

The American journal of surgical pathology. 2005 ; 29 (2) : 230-240.

PMID 15644781

t6;11 renal cell tumor. A clinicopathologic study of 2 cases in adults.

Martignoni G, Tardanico R, Pea M, Pecciarini L, Gobbo S, Brunelli M, Balzarini P, Macri E, Doglioni C

Mod Pathol. 2005 ; 18.

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(6;11)(p21;q12) in renal cell carcinoma. Atlas Genet Cytogenet Oncol Haematol. April 2005 .
URL : http://AtlasGeneticsOncology.org/Genes/RenalCellt0611ID5011.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Mon Aug 11 21:22:26 2008

Home Genes Leukemias Solid Tumours Cancer-Prone Deep Insight Case Reports Journals Portal Teaching

For comments and suggestions or contributions, please contact us

j.l.huret@chu-poitiers.fr.

Other names	Alpha-TFEB renal cell carcinoma
Note	A distinctive renal neoplasm with epithelioid morphology, basement membrane production focal HMB45 immunoreactivity.

Etiology	Not clear, but two of 12 confirmed cases have occurred in children who were exposed to prior cytotoxic chemotherapy, raising the possibility that this tumor may be induced by chemotherapy.
Epidemiology	There are 12 reported cases, 3 in males and 9 in females. The median age is 18 years (range: 6-53 years).
Pathology	On microscopic examination, these neoplasms feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Papillary architecture may be seen. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders and round nuclei with small nucleoli. However, a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini. Mitoses are rare and necrosis is usually absent. The cases examined have generally been negative for cytokeratins by immunohistochemistry, but all have labeled at least focally for HMB45 and Melan A. We have recently found that the t(6;11) renal carcinomas demonstrate specific nuclear labeling for TFEB protein by IHC while other neoplasms and normal tissues do not. Hence, nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this renal neoplasm with a TFEB gene fusion.


Treatment	Nephrectomy
Prognosis	Unclear at the current time. One case has metastasized and killed the patient, proving that these are malignant neoplasms.

Gene Name	TFEB
Location	6p21
Dna / Rna	TFEB has 10 exons, with the ATG protein initiation codon located within exon 3.
Protein	TFEB is a transcription factor with a basic helix-loop-helix DNA binding domain, a leucine zipper dimerization domain18, and a nuclear localization signal, thought to be located C-terminal to the helix-loop-helix domain. TFEB is ubiquitously expressed. TFEB, TFE3, 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	Alpha
Location	11q12
Dna / Rna	Alpha is an intronless, untranslated gene of unknown function.

Hybrid Gene
Description	The breakpoint on TFEB is within its second intron, just upstream of the TFEB initiation ATG codon, which results in retention of the entire TFEB coding region in the fusion gene. Although the Alpha promoter drives expression of the fusion gene, the Alpha gene does not contribute to the open reading frame. Therefore, the consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. The TFEB-Alpha fusion gene is also expressed.
Detection	RT-PCR is the standard molecular approach for detection of most translocation-associated gene fusions. This is because, in most leukemia and sarcoma translocations, genomic breakpoints are variably positioned within large introns, but the splicing of the transcripts encoded by fusion genes typically results in very consistent fusion points that can be tightly bracketed by appropriate primers to generate relatively small RT-PCR products (e.g. 100-300 bp). In the t(6;11)(p21;q12), the lack of splicing between Alpha and TFEB results in a different and unique fusion transcript in each case that can vary considerably in size (over 1 kb) from case to case. Since RNAs extracted from clinical samples are usually partially degraded, amplification of targets in this size range is much more inefficient and the risk of false-negatives correspondingly increases. The Alpha fusion points in 7 fully characterized tumors were scattered over 1.2 kb. Because there are likely no functional consequences to different fusion points in Alpha (since it does not encode a native protein or a fusion protein with TFEB), additional Alpha fusion points outside of this breakpoint cluster region may well be found in the future. The fusion points in TFEB appear more tightly clustered; so far, all have been located in a 167 bp region near the 3¹end of intron 2. Based on the sizes of these two breakpoint cluster regions, RT-PCR product sizes using a primer at the 5¹ end of Alpha in combination with a reverse primer in exon 3 of TFEB could range in size to over 1.5 kb. This is a technical drawback for molecular diagnosis that could be addressed by using several assays with different Alpha primers scattered from the 5¹ to the 3¹ end of the gene. However the unique features of the Alpha gene as a translocation partner should result in a lack of splicing across the intron rearranged by the translocation. Indeed, this seems to be the case, since in all three cases with data on both the genomic junction sequence and the fusion transcript, the sequences have been identical. This indicates that the DNA PCR and RT-PCR products will be identical if a reverse primer that binds to TFE3 exon 3 is used. Because it is easier to isolate and amplify 1 to 1.5 kb target DNAs from clinical tumor samples than target RNAs of the same size (given the greater lability of RNA), detecting this fusion by long range DNA PCR may be a useful alternative for molecular diagnosis.
Fusion Protein
Note	The Alpha-TFEB gene fusion results in dysregulated expression of native TFEB protein.
Expression Localisation	TFEB protein that is overexpressed as a result of the Alpha-TFEB gene fusion localizes to the nucleus as determined by immunohistochemistry. While it is ubiquitously expressed, native TFEB in cells without this translocation is not detectable by this assay.

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