The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25

Marc Ladanyi, Man Yee Lui, Cristina R. Antonescu, Amber Krause-Boehm, Alfons Meindl, Pedram Argani, John H. Healey, Takafumi Ueda, Hideki Yoshikawa, Aurelia Meloni-Ehrig, Poul H B Sorensen, Fredrik Mertens, Nils Mandahl, Herman Van Den Berghe, Raf Sciot, Paola Dal Cin, Julia Bridge

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Abstract

Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12:9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocationassociated sarcomas.

Original languageEnglish (US)
Pages (from-to)48-57
Number of pages10
JournalOncogene
Volume20
Issue number1
DOIs
StatePublished - Jan 4 2001

Fingerprint

Alveolar Soft Part Sarcoma
Transcription Factors
Genes
Exons
Sarcoma
Complementary DNA
Cosmids
Chromosomes, Human, Pair 17
Expressed Sequence Tags
Southern Blotting
Reverse Transcriptase Polymerase Chain Reaction
Renal Cell Carcinoma
Cytogenetics
Open Reading Frames
Neoplasms
Proteins
Amino Acids
DNA

Keywords

  • Chromosomal translocation
  • Gene fusion
  • Molecular diagnosis
  • Soft tissue sarcoma
  • UBX domain

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ladanyi, M., Lui, M. Y., Antonescu, C. R., Krause-Boehm, A., Meindl, A., Argani, P., ... Bridge, J. (2001). The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene, 20(1), 48-57. https://doi.org/10.1038/sj.onc.1204074

The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. / Ladanyi, Marc; Lui, Man Yee; Antonescu, Cristina R.; Krause-Boehm, Amber; Meindl, Alfons; Argani, Pedram; Healey, John H.; Ueda, Takafumi; Yoshikawa, Hideki; Meloni-Ehrig, Aurelia; Sorensen, Poul H B; Mertens, Fredrik; Mandahl, Nils; Van Den Berghe, Herman; Sciot, Raf; Dal Cin, Paola; Bridge, Julia.

In: Oncogene, Vol. 20, No. 1, 04.01.2001, p. 48-57.

Research output: Contribution to journalArticle

Ladanyi, M, Lui, MY, Antonescu, CR, Krause-Boehm, A, Meindl, A, Argani, P, Healey, JH, Ueda, T, Yoshikawa, H, Meloni-Ehrig, A, Sorensen, PHB, Mertens, F, Mandahl, N, Van Den Berghe, H, Sciot, R, Dal Cin, P & Bridge, J 2001, 'The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25', Oncogene, vol. 20, no. 1, pp. 48-57. https://doi.org/10.1038/sj.onc.1204074
Ladanyi, Marc ; Lui, Man Yee ; Antonescu, Cristina R. ; Krause-Boehm, Amber ; Meindl, Alfons ; Argani, Pedram ; Healey, John H. ; Ueda, Takafumi ; Yoshikawa, Hideki ; Meloni-Ehrig, Aurelia ; Sorensen, Poul H B ; Mertens, Fredrik ; Mandahl, Nils ; Van Den Berghe, Herman ; Sciot, Raf ; Dal Cin, Paola ; Bridge, Julia. / The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. In: Oncogene. 2001 ; Vol. 20, No. 1. pp. 48-57.
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abstract = "Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12:9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocationassociated sarcomas.",
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T1 - The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25

AU - Ladanyi, Marc

AU - Lui, Man Yee

AU - Antonescu, Cristina R.

AU - Krause-Boehm, Amber

AU - Meindl, Alfons

AU - Argani, Pedram

AU - Healey, John H.

AU - Ueda, Takafumi

AU - Yoshikawa, Hideki

AU - Meloni-Ehrig, Aurelia

AU - Sorensen, Poul H B

AU - Mertens, Fredrik

AU - Mandahl, Nils

AU - Van Den Berghe, Herman

AU - Sciot, Raf

AU - Dal Cin, Paola

AU - Bridge, Julia

PY - 2001/1/4

Y1 - 2001/1/4

N2 - Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12:9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocationassociated sarcomas.

AB - Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5′ portion of cDNAs containing the 3′ portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12:9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocationassociated sarcomas.

KW - Chromosomal translocation

KW - Gene fusion

KW - Molecular diagnosis

KW - Soft tissue sarcoma

KW - UBX domain

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