Array-based comparative genomic hybridization identifies CDK4 and FOXM1 alterations as independent predictors of survival in malignant peripheral nerve sheath tumor

Clin Cancer Res. 2011 Apr 1;17(7):1924-34. doi: 10.1158/1078-0432.CCR-10-1551. Epub 2011 Feb 16.

Abstract

Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Biomarkers, Tumor / genetics*
  • Child
  • Comparative Genomic Hybridization
  • Cyclin-Dependent Kinase 4 / genetics*
  • Female
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / genetics*
  • Gene Dosage
  • Gene Duplication
  • Genetic Association Studies
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kaplan-Meier Estimate
  • Male
  • Membrane Proteins / genetics
  • Middle Aged
  • Multivariate Analysis
  • Neoplasm Recurrence, Local
  • Nerve Sheath Neoplasms / diagnosis*
  • Nerve Sheath Neoplasms / genetics
  • Nerve Sheath Neoplasms / mortality
  • Nuclear Proteins / genetics
  • Prognosis
  • Proportional Hazards Models
  • Proto-Oncogene Proteins c-myc / genetics
  • Receptor, ErbB-2 / genetics
  • SOXD Transcription Factors / genetics
  • Tacrolimus Binding Protein 1A / genetics
  • Tetraspanins
  • Transcription, Genetic
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult
  • tRNA Methyltransferases / genetics

Substances

  • Biomarkers, Tumor
  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • MLF2 protein, human
  • MYC protein, human
  • Membrane Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-myc
  • SOX5 protein, human
  • SOXD Transcription Factors
  • TP53 protein, human
  • TSPAN31 protein, human
  • Tetraspanins
  • Tumor Suppressor Protein p53
  • NOP2 protein, human
  • tRNA Methyltransferases
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4
  • Tacrolimus Binding Protein 1A