Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas Journal Article
| Authors: | Lae, M.; Ahn, E. H.; Mercado, G. E.; Chuai, S.; Edgar, M.; Pawel, B. R.; Olshen, A.; Barr, F. G.; Ladanyi, M. |
| Article Title: | Global gene expression profiling of PAX-FKHR fusion-positive alveolar and PAX-FKHR fusion-negative embryonal rhabdomyosarcomas |
| Abstract: | Paediatric rhabdomyosarcomas (RMS) are classified into two major subtypes based on histological appearance, embryonal (ERMS) and alveolar (ARMS), but this clinically critical distinction is often difficult on morphological grounds alone. ARMS, the more aggressive subtype, is associated in most cases with unique recurrent translocations fusing the PAX3 or PAX7 transcription factor genes to FKHR. In contrast, ERMS lacks unique genetic alterations. To identify novel diagnostic markers and potential therapeutic targets, we analysed the global gene expression profiles of these two RMS subtypes in 23 ARMS (16 PAX3-FKHR, 7 PAX7-FKHR) and 15 ERMS (all PAX-FKHR-negative) using Affymetrix HG-U133A oligonucleotide arrays. A statistically stringent supervised comparison of the ARMS and ERMS expression profiles revealed 121 genes that were significantly differentially expressed, of which 112 were higher in ARMS, including genes of interest as potential diagnostic markers or therapeutic targets, such as CNR1, PIPOX (sarcosine oxidase), and TFAP β. Interestingly, many known or putative downstream targets of PAX3-FKHR were highly overexpressed in ARMS relative to ERMS, including CNR1, DCX, ABAT, ASS, JAKMIP2, DKFZp762M127, and NRCAM. We validated the highly differential expression of five genes, including CNR1, DKPZp762M127, DCX, PIPOX, and FOXF1 in ARMS relative to ERMS by quantitative RT-PCR on an independent set of samples. Finally, we developed a ten-gene microarray-based predictor that distinguished ARMS from ERMS with approximately 95% accuracy both in our data by cross-validation and in an independent validation using a published dataset of 26 samples. The gene expression signature of ARMS provides a source of potential diagnostic markers, therapeutic targets, and PAX-FKHR downstream genes, and can be used to reliably distinguish these sarcomas from ERMS. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| Keywords: | child; controlled study; human tissue; unclassified drug; validation process; diagnostic accuracy; forkhead transcription factors; gene targeting; gene overexpression; reverse transcription polymerase chain reaction; gene expression; gene expression profiling; neoplasm proteins; gene product; transcription factor; prediction; sarcoma; molecular marker; gene expression regulation, neoplastic; reverse transcriptase polymerase chain reaction; oligonucleotide array sequence analysis; gene fusion; oncogene proteins, fusion; translocation, genetic; dna flanking region; dna microarray; transcription factor pax3; microarray; rhabdomyosarcoma; embryonal rhabdomyosarcoma; rhabdomyosarcoma, embryonal; genetic markers; skeletal muscle; paired box transcription factor; paired box transcription factors; rhabdomyosarcoma, alveolar; transcription factor fkhr; translocation; transcription factor pax7; pax7 transcription factor; transcription factor ap 2; 4 aminobutyrate aminotransferase; argininosuccinate synthase; cannabinoid 1 receptor; dkfzp762m127 protein; jak and microtubule interacting protein 2; sarcosine oxidase; transcription factor foxf1 |
| Journal Title: | Journal of Pathology |
| Volume: | 212 |
| Issue: | 2 |
| ISSN: | 0022-3417 |
| Publisher: | Wiley Blackwell |
| Date Published: | 2007-06-01 |
| Start Page: | 143 |
| End Page: | 151 |
| Language: | English |
| DOI: | 10.1002/path.2170 |
| PUBMED: | 17471488 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 36" - "Export Date: 17 November 2011" - "CODEN: JPTLA" - "Source: Scopus" |
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