Data from Array-Based Comparative Genomic Hybridization Identifies <i>CDK4</i> and <i>FOXM1</i> Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor

Abstract

<div>Abstract<p><b>Purpose:</b> 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.</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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 <i>SOX5</i> (12p12.1), <i>NOL1</i> and <i>MLF2</i> (12p13.31), <i>FOXM1</i> and <i>FKBP1</i> (12p13.33), and <i>CDK4</i> and <i>TSPAN31</i> (12q14.1). Alterations of these candidate genes and several others of interest (<i>ERBB2, MYC and TP53)</i> were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence <i>in situ</i> hybridization and immunohistochemistry. Multivariate analysis showed that <i>CDK4</i> gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (<i>P</i> < 0.05).</p><p><b>Conclusions:</b> Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. <i>Clin Cancer Res; 17(7); 1924–34. ©2011 AACR</i>.</p></div>