Array-Based Comparative Genomic Hybridization Identifies CDK4 and FOXM1 Alterations as Independent Predictors of Survival in Malignant Peripheral Nerve Sheath Tumor

Jinsheng Yu,Jacqueline E Payton,Christopher Dunham,David H Gutmann,Arie Perry,Ryan J Emnett,Abhijit Guha,Mark A Watson,Rebecca J Gutmann,Rosalie E Ferner,Lorena Salavaggione,Guy M Lindberg,Hrishikesh Deshmukh,Tarik Tihan,Julia A Bridge,Rakesh Nagarajan,Bernd W Scheithauer,Richard A Prayson

doi:10.1158/1078-0432.ccr-10-1551

Abstract

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. 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. 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). Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients.

Highlights

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive and frequently lethal Schwann cellderived neoplasms associated with poor survival [1,2,3,4,5]
Through initial identification of several survival-associated copy number alterations, followed by confirmatory assays and a comprehensive multivariate analysis, our present study demonstrates that CDK4 gain/amplification and increased FOXM1 protein expression are significant independent predictors for poor survival in MPNST patients
The results from this study provide a short list of candidate genes with copy number alterations (CNA) which may prove clinically useful as prognostic biomarkers for patients with MPNST

Summary

Introduction

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive and frequently lethal Schwann cellderived neoplasms associated with poor survival [1,2,3,4,5]. Half of MPNSTs develop sporadically and the other half arise in the setting of neurofibromatosis type 1 (NF1). The 5-year survival rate for NF1-associated MPNST patients is reportedly half of that for sporadic cases (21% vs 42%; ref 5). Other studies suggest that a diagnosis of NF1 does not affect survival [6]. Clinicopathologic factors, such as tumor grade and anatomic site reportedly influence MPNST patient outcome, the clinical course remains highly variable and difficult to predict in individual patients.

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