Gene Expression Signatures Identify Rhabdomyosarcoma Subtypes and Detect a Novel t(2;2)(q35;p23) Translocation Fusing PAX3 to NCOA1

Wachtel, Marco; Dettling, Marcel; Koscielniak, Eva; Stegmaier, Sabine; Treuner, J.; Simon-Klingenstein, Katja; Bühlmann, Peter; Niggli, Felix; Schäfer, Beat W.

doi:10.1158/0008-5472.can-04-0844

Cited by 224 publications

(214 citation statements)

References 21 publications

Supporting

Mentioning

198

Contrasting

Unclassified

Order By: Relevance

“…Two PAX3 variant translocations have been previously described: PAX3-AFX and PAX3-NCOA1. 6,7 Our FISH studies suggest that one of the discordant cases, Case 13, also represents a PAX3 variant translocation. FISH analysis of this case revealed rearrangement of the PAX3 gene with no fusion of signals occurring between the PAX3 and FKHR gene loci.…”

Section: Discussionmentioning

confidence: 72%

“…4,5 The remaining 20% of ARMS are translocation or fusion-negative forming a basically unexplored group, although two variant translocation associated fusion transcripts (PAX3-AFX and PAX3-NCOA1) have been described. 6,7 Although the different PAX-FKHR fusion genes are readily identified by reverse transcriptase-polymerase chain reaction (RT-PCR), this technique may be limited by RNA quality and failure of devised primer sets to detect unusual variants. Previous FISH studies have been performed on a small series of RMS samples.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

Nishio

Althof

Bailey

et al. 2006

Laboratory Investigation

View full text Add to dashboard Cite

A valuable diagnostic adjunct and important prognostic parameter in alveolar rhabdomyosarcoma (ARMS) is the identification of translocations t(2;13)(q35;q14) and t(1;13)(p36;q14), and the associated PAX3-FKHR and PAX7-FKHR fusion transcripts, respectively. Most RMS fusion gene type studies have been based on reverse transcriptase-polymerase chain reaction (RT-PCR) detection of the fusion transcript, a technique limited by RNA quality and failure of devised primer sets to detect unusual variants. As an alternative approach, we developed a fluorescence in situ hybridization (FISH) assay that can: (1) distinguish between the two most common ARMS-associated fusion genes; (2) identify potential unusual variant translocations; (3) assess histologic components in mixed alveolar/embryonal RMS; and (4) be performed on paraffinized tissue. FISH analyses of 75 specimens (40 ARMS, 16 ERMS, 8 mixed ARMS/ERMS, and 11 non-RMS tumors) using selected cosmid clone, bacterial, P1-derived, and yeast artificial chromosome probe sets were successful in all but two cases. Among specimens with informative results for both FISH and RT-PCR or standard karyotyping, PAX/ FKHR classification results were concordant in 94.6% (53/56). The three discordant cases included one exhibiting a t(2;13) by FISH that was subsequently confirmed by repeat RT-PCR, a second showing a rearrangement of the PAX3 locus only (consistent with the presence of a PAX3 variant translocation), and a third revealing a t(2;13) by FISH that lacked this translocation cytogenetically. Both alveolar and embryonal components of the mixed ARMS/ERMS subtype were negative for PAX3, PAX7, and FKHR rearrangements, a surprising finding confirmed by RT-PCR and/or conventional karyotyping. These data demonstrate that FISH with newly designed probe sets is a reliable and highly specific method of detecting t(1;13) and t(2;13) in routinely processed tissue and may be useful in differentiating ARMS from other small round cell tumors. The findings also suggest that FISH may be a more sensitive assay than RT-PCR in some settings, capable of revealing variant translocations.

show abstract

Section: Discussionmentioning

confidence: 72%

mentioning

confidence: 99%

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

Nishio

Althof

Bailey

et al. 2006

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…The p73-regulated genes are differentially expressed in rhabdomyosarcoma subtypes. The mTOR-p73 gene signature was assessed using a publicly available dataset in which 29 rhabdomyosarcoma tumors were profiled by microarray (14). (A) All genes that changed >20% with rapamycin or p73 RNAi were included in this initial analysis to increase overlap across microarray platforms.…”

Section: Discussionmentioning

confidence: 99%

“…Wachtel et al analyzed the gene expression patterns of 29 primary rhabdomyosarcomas (14). We filtered these tumor data against the mTOR-p73 signature, and used hierarchical clustering to segregate tumors according to the status of the mTOR-p73 signature (Fig.…”

Section: Genes Regulated By Mtor and P73 Classify Rhabdomyosarcomamentioning

confidence: 99%

Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis

Rosenbluth

Mays

Jiang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transcription factor p73 plays critical roles during development and tumorigenesis. It exhibits sequence identity and structural homology with p53, and can engage p53-like tumor-suppressive programs. However, different pathways regulate p53 and p73, and p73 is not mutated in human tumors. Therefore, p73 represents a therapeutic target, and there is a critical need to understand genes and noncoding RNAs regulated by p73 and how they change during treatment regimens. Here, we define the p73 genomic binding profile and demonstrate its modulation by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) and inducer of p73. Rapamycin selectively increased p73 occupancy at a subset of its binding sites. In addition, multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR. We generated an mTOR-p73 signature that is enriched for p73 target genes and miRNAs that are involved in mesenchymal differentiation and tumorigenesis, can classify rhabdomyosarcomas by clinical subtype, and can predict patient outcome.p63 | ChIP-on-Chip | stem cell | muscle | consensus binding site

show abstract

“…[12][13][14] Among a number of different cancer types, few studies were conducted in ARMS cell lines to define the gene expression profile and the influence of the exogenously expressed fusion gene PAX3-FKHR 15,16 and more recently in ARMS and ERMS tumors. [17][18][19] To better characterize the pattern of gene activation in ARMS we analyzed a series of tumor specimens by using a novel version of the cDNA microarray platform previously established in our laboratory. 20,21 We also studied the differential gene expression profile of PAX3-FKHR positive and negative ARMS.…”

mentioning

confidence: 99%

Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3‐FKHR positive and negative tumors

Pittà

Tombolan

Albiero

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

We analyzed the expression signatures of 14 tumor biopsies from children affected by alveolar rhabdomyosarcoma (ARMS) to identify genes correlating to biological features of this tumor. Seven of these patients were positive for the PAX3-FKHR fusion gene and 7 were negative. We used a cDNA platform containing a large majority of probes derived from muscle tissues. The comparison of transcription profiles of tumor samples with fetal skeletal muscle identified 171 differentially expressed genes common to all ARMS patients. The functional classification analysis of altered genes led to the identification of a group of transcripts (LGALS1, BIN1) that may be relevant for the tumorigenic processes. The muscle-specific microarray platform was able to distinguish PAX3-FKHR positive and negative ARMS through the expression pattern of a limited number of genes (RAC1, CFL1, CCND1, IGFBP2) that might be biologically relevant for the different clinical behavior and aggressiveness of the 2 ARMS subtypes. Expression levels for selected candidate genes were validated by quantitative real-time reverse-transcription PCR. ' 2005 Wiley-Liss, Inc.Key words: alveolar rhabdomyosarcoma; microarray; gene expression profiling; PAX3-FKHR Rhabdomyosarcomas (RMS) are rare but very aggressive tumors of childhood. It is generally hypothesized that these tumors arise as a consequence of regulatory disruption of the growth and differentiation pathways of myogenic precursor cells, but the actual identity of this precursor is still a matter of debate and research. 1,2 Based on morphology, 2 major RMS subtypes can be identified: embryonal RMS (ERMS) and alveolar RMS (ARMS). The embryonal RMS includes also the botryoid, anaplastic and spindle-cell variants. An additional subtype is the pleomorphic RMS, which is exceptionally found in childhood. 3 ARMS represents approximately 25-30% of RMS and has a worse prognosis than ERMS. Cytogenetic and molecular analyses have demonstrated that ARMS frequently harbor the reciprocal chromosomal translocation t(2;13)(q35;q14), in which the PAX3 and FKHR genes are juxtaposed; also the less frequent variant translocation t(1;13)(p36;q14) has been associated to ARMS. The PAX3-FKHR chimeric protein binds regulatory sequences of genes involved in growth, differentiation, apoptosis and in vivo migration of rhabdomyoblasts, including c-met, IGF-1, PDGF-R, BCL-X, SDF-1 and CXCR4. [4][5][6][7][8] Moreover, retrospective analysis of PAX3-FKHR positive and negative ARMS 9-11 suggested that the translocation positive ARMS patients fared worse than the negative counterpart. Thus, the presence of the t(2;13) reciprocal translocation should be considered one of the main features affecting the biology of ARMS cells and might represent an adverse prognostic factor.Recently, the genomic approach based on global gene expression profiling by DNA microarrays has seen an explosive number of applications for cancer classification, prognosis and functional analysis of gene networks implicated in cancer biology. [12][13][14] Among a num...

show abstract

Gene Expression Signatures Identify Rhabdomyosarcoma Subtypes and Detect a Novel t(2;2)(q35;p23) Translocation Fusing PAX3 to NCOA1

Cited by 224 publications

References 21 publications

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

Use of a novel FISH assay on paraffin-embedded tissues as an adjunct to diagnosis of alveolar rhabdomyosarcoma

Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis

Gene expression profiling identifies potential relevant genes in alveolar rhabdomyosarcoma pathogenesis and discriminates PAX3‐FKHR positive and negative tumors

Contact Info

Product

Resources

About