Variant Translocations of Chromosome 13 in Alveolar Rhabdomyosarcoma

Douglass, Edwin C.; Rowe, Susan; Valentine, Marc; Parham, David M.; Berkow, Roger L.; Bowman, W. Paul; Maurer, Harold M.

doi:10.1002/gcc.2870030611

Cited by 69 publications

(26 citation statements)

References 3 publications

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“…The most prevalent ®nding in ARMS is a translocation, t(2;13)(q35-37;q14), which was detected in 70% of ARMS cases (Douglass et al, 1987;Turc-Carel et al, 1986;Wang-Wuu et al, 1988) (Figure 1). In addition, a variant translocation, t(1;13)(p36;q14), was identi®ed in a smaller subset of ARMS cases (Biegel et al, 1991;Oncogene (2001) 20, 5736 ± 5746 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc *Correspondence: FG Barr; E-mail: barrfg@mail.med.upenn.edu Douglass et al, 1991). The 2;13 and 1;13 translocations have not been detected in any other tumor type and appear to be speci®c and sensitive markers of ARMS.…”

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confidence: 99%

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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The chromosomal translocations t(2;13)(q35;q14) and t(1;13)(p36;q14) are characteristic of alveolar rhabdomyosarcoma, a pediatric soft tissue cancer related to the striated muscle lineage. These translocations rearrange PAX3 and PAX7, members of the paired box transcription factor family, and juxtapose these genes with FKHR, a member of the fork head transcription factor family. This juxtaposition generates PAX3 ± FKHR and PAX7 ± FKHR chimeric genes that are expressed as chimeric transcripts that encode chimeric proteins. The fusion proteins, which contain the PAX3/PAX7 DNA binding domain and the FKHR transcriptional activation domain, activate transcription from PAX-binding sites with higher potency than the corresponding wild-type PAX proteins. This increased function results from the insensitivity of the FKHR activation domain to inhibitory e ects of N-terminal PAX3/PAX7 domains. In addition to altered function, the fusion products are expressed in ARMS tumors at higher levels than the corresponding wild-type PAX products due to two distinct mechanisms. The PAX7 ± FKHR fusion is overexpressed as a result of in vivo ampli®cation while the PAX3 ± FKHR fusion is overexpressed due to a copy number-independent increase in transcriptional rate. Finally, though FKHR subcellular localization is regulated by an AKTdependent pathway, the fusion proteins are resistant to these signals and show exclusively nuclear localization. Therefore, these translocations alter biological activity at the levels of protein function, gene expression, and subcellular localization with the cumulative outcome postulated to be aberrant regulation of PAX3/PAX7 target genes. This aberrant gene expression program is then hypothesized to contribute to tumorigenic behavior by impacting on the control of growth, apoptosis, di erentiation and motility. Oncogene (2001) 20, 5736 ± 5746.

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confidence: 99%

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

2001

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“…Therefore, it was suggested that these abnormalities, taken together, might have a significant role in the genesis of the tumor (Magnani et al, 1991). The occurrence of a t(1;13)(p36;q14) is not an uncommon finding in RMS (Biegel et al, 1991;Douglass et al, 1991). It has been described that this translocation results in the formation of a chimeric protein consisting of part of the PAX7 gene on chromosome 1 and the FOXO1A (FKHR) gene on chromosome 13 (Davis et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Delineation and physical separation of novel translocation breakpoints on chromosome 1p in two genetically closely associated childhood tumors

Steenman

Zijlstra

Kruitbosch

et al. 2000

Cytogenet Genome Res

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Sporadic childhood tumors associated with Beckwith-Wiedemann syndrome (BWS) all show abnormalities of the same region on chromosome 11. In addition to chromosome 11, other chromosome regions are affected in some of these tumor types. In this study we analyzed the region on chromosome 1p involved in the etiology of BWS-associated tumors, Wilms tumor, rhabdomyosarcoma, and hepatoblastoma. For this purpose we determined the location of two novel translocation breakpoints in this chromosome region in cells from a Wilms tumor and cells from a rhabdomyosarcoma. We constructed a map of the region and found that both breakpoints are separated by at least 875 kb. We identified a PAC clone which crosses the rhabdomyosarcoma breakpoint and found several exons within this clone. We established that this breakpoint is located proximal to the PAX7 gene and, therefore, identified a new region involved in the etiology of rhabdomyosarcomas.

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“…Two cases of solid A-RMS have also been described with a t(2;13) (Parham et al, 1994). A minority of cases contain variants of this translocation; the most common being a t(1;13)(p36.1;q14) (Biegel et al, 1991;Dal Cin et al, 1991;Douglass et al, 1991;Whang-Peng et al, 1992). A study correlating karyotype with clinical characteristics determined that patients with a t(2;13) were older and that the tumors were located in the trunk (Douglass et al, 1993).…”

Section: Embryonal Rms (E-rms) Alveolar Rms (A-rms) and Pleomorphic mentioning

confidence: 99%

The cytogenetic and molecular characterization of benign and malignant soft tissue tumors

Sreekantaiah

1998

Cytogenet Genome Res

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Cytogenetic analyses of benign and malignant soft tissue tumors have led to the description of recurrent, specific, and even pathognomonic chromosomal translocations and/or other rearrangements in most types of soft tissue tumors. The consistent karyotypic rearrangements have provided critical diagnostic information in this group of neoplasms that often presents significant diagnostic challenges to the clinician and the pathologist. These findings have also been instrumental in the characterization of the abnormalities at the molecular level. Novel genes have been isolated from the translocation junctions and the mechanisms of their deregulation identified. This has increased our understanding of the histogenesis of these tumors, paved the way for the molecular diagnosis of many sarcomas, aided in directing therapy, and also provided important prognostic information.

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Variant Translocations of Chromosome 13 in Alveolar Rhabdomyosarcoma

Cited by 69 publications

References 3 publications

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma

Delineation and physical separation of novel translocation breakpoints on chromosome 1p in two genetically closely associated childhood tumors

The cytogenetic and molecular characterization of benign and malignant soft tissue tumors

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