title: PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification.
abstract: OBJECTIVE
  To improve the risk stratification of patients with rhabdomyosarcoma (RMS) through the use of clinical and molecular biologic data.
  
  
  METHODS
  Two independent data sets of gene-expression profiling for 124 and 101 patients with RMS were used to derive prognostic gene signatures by using a meta-analysis. These and a previously published metagene signature were evaluated by using cross validation analyses. A combined clinical and molecular risk-stratification scheme that incorporated the PAX3/FOXO1 fusion gene status was derived from 287 patients with RMS and evaluated.
  
  
  RESULTS
  We showed that our prognostic gene-expression signature and the one previously published performed well with reproducible and significant effects. However, their effect was reduced when cross validated or tested in independent data and did not add new prognostic information over the fusion gene status, which is simpler to assay. Among nonmetastatic patients, patients who were PAX3/FOXO1 positive had a significantly poorer outcome compared with both alveolar-negative and PAX7/FOXO1-positive patients. Furthermore, a new clinicomolecular risk score that incorporated fusion gene status (negative and PAX3/FOXO1 and PAX7/FOXO1 positive), Intergroup Rhabdomyosarcoma Study TNM stage, and age showed a significant increase in performance over the current risk-stratification scheme.
  
  
  CONCLUSIONS
  Gene signatures can improve current stratification of patients with RMS but will require complex assays to be developed and extensive validation before clinical application. A significant majority of their prognostic value was encapsulated by the fusion gene status. A continuous risk score derived from the combination of clinical parameters with the presence or absence of PAX3/FOXO1 represents a robust approach to improving current risk-adapted therapy for RMS.
authors.affiliation: The Institute of Cancer Research, Sutton, Surrey, UK.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Missiaglia
authors.forename: Dan
authors.initials: D
authors.lastname: Williamson
authors.forename: Julia
authors.initials: J
authors.lastname: Chisholm
authors.forename: Pratyaksha
authors.initials: P
authors.lastname: Wirapati
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Pierron
authors.forename: Fabien
authors.initials: F
authors.lastname: Petel
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Concordet
authors.forename: Khin
authors.initials: K
authors.lastname: Thway
authors.forename: Odile
authors.initials: O
authors.lastname: Oberlin
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones
authors.forename: Olivier
authors.initials: O
authors.lastname: Delattre
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.forename: Janet
authors.initials: J
authors.lastname: Shipley
mesh_terms: D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000401:mortality* / Q000628:therapy; D012308:Risk Management; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D014178:Translocation, Genetic; D006113:United Kingdom
chemical_list: D014408:Biomarkers, Tumor; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors