Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Anderson, John; Gordon, Tony; McManus, Aidan; Mapp, Trudell; Gould, Steve; Kelsey, Anna; McDowell, Heather P.; Pinkerton, Ross; Shipley, Janet; Pritchard‐Jones, Kathy

doi:10.1054/bjoc.2001.2008

Cited by 103 publications

(63 citation statements)

References 19 publications

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“…One of the fusion proteins EWS͞FLI-1 or EWS͞ERG is overexpressed from chromosomal translocation in EWS (15). One of the fusion proteins PAX3͞FKHR or PAX7͞FKHR is expressed in RMS (16). We could find only three of the aforementioned genes in the cDNA microarray of ref.…”

Section: Discussionmentioning

confidence: 99%

Diagnosis of multiple cancer types by shrunken centroids of gene expression

Tibshirani

Hastie

Narasimhan

et al. 2002

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

2,504

2,250

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We have devised an approach to cancer class prediction from gene expression profiling, based on an enhancement of the simple nearest prototype (centroid) classifier. We shrink the prototypes and hence obtain a classifier that is often more accurate than competing methods. Our method of ''nearest shrunken centroids'' identifies subsets of genes that best characterize each class. The technique is general and can be used in many other classification problems. To demonstrate its effectiveness, we show that the method was highly efficient in finding genes for classifying small round blue cell tumors and leukemias.

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Section: Discussionmentioning

confidence: 99%

Diagnosis of multiple cancer types by shrunken centroids of gene expression

Tibshirani

Hastie

Narasimhan

et al. 2002

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

2,504

2,250

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“…Functional annotation was done using the Expression Analysis Systematic Explorer (EASE) 8 software package for overrepresentation analysis of functional gene categories and for multidatabase annotation of the differentially expressed genes (29). Pathway analysis was done with the online Ingenuity Pathways analysis (IPA) tool (version 3.0; ref.…”

Section: Methodsmentioning

confidence: 99%

“…In fact, it seems that these fusion-negative ARMS tumors are more similar to ERMS tumors with respect to other covariates, such as age at diagnosis and patient survival (7). Furthermore, there are indications that PAX3-FKHR and PAX7-FKHR ARMS tumors represent high-and low-risk subgroups, respectively, among patients presenting with metastatic disease (6,8). Lastly, there are a few rhabdomyosarcoma tumors displaying mixed alveolar/embryonal histology.…”

Section: Introductionmentioning

confidence: 99%

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas

Davicioni¹,

et al. 2006

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Alveolar rhabdomyosarcomas (ARMS) are aggressive softtissue sarcomas affecting children and young adults. Most ARMS tumors express the PAX3-FKHR or PAX7-FKHR (PAX-FKHR) fusion genes resulting from the t(2;13) or t(1;13) chromosomal translocations, respectively. However, up to 25% of ARMS tumors are fusion negative, making it unclear whether ARMS represent a single disease or multiple clinical and biological entities with a common phenotype. To test to what extent PAX-FKHR determine class and behavior of ARMS, we used oligonucleotide microarray expression profiling on 139 primary rhabdomyosarcoma tumors and an in vitro model. We found that ARMS tumors expressing either PAX-FKHR gene share a common expression profile distinct from fusion-negative ARMS and from the other rhabdomyosarcoma variants. We also observed that PAX-FKHR expression above a minimum level is necessary for the detection of this expression profile. Using an ectopic PAX3-FKHR and PAX7-FKHR expression model, we identified an expression signature regulated by PAX-FKHR that is specific to PAX-FKHR-positive ARMS tumors. Data mining for functional annotations of signature genes suggested a role for PAX-FKHR in regulating ARMS proliferation and differentiation. Cox regression modeling identified a subset of genes within the PAX-FKHR expression signature that segregated ARMS patients into three risk groups with 5-year overall survival estimates of 7%, 48%, and 93%. These prognostic classes were independent of conventional clinical risk factors. Our results show that PAX-FKHR dictate a specific expression signature that helps define the molecular phenotype of PAX-FKHR-positive ARMS tumors and, because it is linked with disease outcome in ARMS patients, determine tumor behavior.

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“…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][10][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.…”

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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

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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...

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Detection of the PAX3-FKHR fusion gene in paediatric rhabdomyosarcoma: a reproducible predictor of outcome?

Cited by 103 publications

References 19 publications

Diagnosis of multiple cancer types by shrunken centroids of gene expression

Diagnosis of multiple cancer types by shrunken centroids of gene expression

Identification of a PAX-FKHR Gene Expression Signature that Defines Molecular Classes and Determines the Prognosis of Alveolar Rhabdomyosarcomas

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

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