title: Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor.
abstract: OBJECTIVE
  Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs.
  
  
  METHODS
  Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens.
  
  
  RESULTS
  aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05).
  
  
  CONCLUSIONS
  Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Yu
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Deshmukh
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Payton
authors.forename: Christopher
authors.initials: C
authors.lastname: Dunham
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Scheithauer
authors.forename: Tarik
authors.initials: T
authors.lastname: Tihan
authors.forename: Richard A
authors.initials: RA
authors.lastname: Prayson
authors.forename: Abhijit
authors.initials: A
authors.lastname: Guha
authors.forename: Julia A
authors.initials: JA
authors.lastname: Bridge
authors.forename: Rosalie E
authors.initials: RE
authors.lastname: Ferner
authors.forename: Guy M
authors.initials: GM
authors.lastname: Lindberg
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Gutmann
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Emnett
authors.forename: Lorena
authors.initials: L
authors.lastname: Salavaggione
authors.forename: David H
authors.initials: DH
authors.lastname: Gutmann
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagarajan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Watson
authors.forename: Arie
authors.initials: A
authors.lastname: Perry
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D002648:Child; D055028:Comparative Genomic Hybridization; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018628:Gene Dosage; D020440:Gene Duplication; D056726:Genetic Association Studies; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000401:mortality; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D055755:SOXD Transcription Factors / Q000235:genetics; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics; D059470:Tetraspanins; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult; D012359:tRNA Methyltransferases / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D051358:Cyclin-Dependent Kinase 4; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D018719:Erb-b2 Receptor Tyrosine Kinases; D055755:SOXD Transcription Factors; D022061:Tacrolimus Binding Protein 1A; D059470:Tetraspanins; D016159:Tumor Suppressor Protein p53; D012359:tRNA Methyltransferases; C107585:FOXM1 protein, human; C100853:MLF2 protein, human; C489427:MYC protein, human; C490301:SOX5 protein, human; C495901:TP53 protein, human; C086385:TSPAN31 protein, human; C065028:NOP2 protein, human; C508053:ERBB2 protein, human; C495900:CDK4 protein, human