High-Resolution DNA Copy Number Profiling of Malignant Peripheral Nerve Sheath Tumors Using Targeted Microarray-Based Comparative Genomic Hybridization

• Published in: Clinical cancer research Vol. 14; no. 4; pp. 1015 - 1024
• Main Authors: Mantripragada, Kiran K., Spurlock, Gillian, Kluwe, Lan, Chuzhanova, Nadia, Ferner, Rosalie E., Frayling, Ian M., Dumanski, Jan P., Guha, Abhijit, Mautner, Victor, Upadhyaya, Meena
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2008
• Subjects: Antineoplastic agents; array CGH; Biological and medical sciences; Biomarkers, Tumor - genetics; Gene Dosage; Gene Expression Profiling; Humans; Image Processing, Computer-Assisted; Medical sciences; microarray; MPNST; Nerve Sheath Neoplasms - genetics; Neurofibroma - genetics; neurofibromatosis; Neurofibromatosis 1 - complications; Neurofibromatosis 1 - genetics; Neurology; NF1; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Tumors of the nervous system. Phacomatoses; Peripheral nerve; Nervous system diseases; High resolution; Targeting; Copy number; Neurinoma; Malignant tumor; Gene expression; Target; Comparative genomic hybridization; DNA; Benign neoplasm; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-1305

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant condition that predisposes to benign and malignant tumors. The lifetime risk of a malignant peripheral nerve sheath tumor (MPNST) in NF1 is ∼10%. These tumors have a poor survival rate and their molecular basis remains unclear. We report the first comprehensive investigation of DNA copy number across multitude of genes in NF1 tumors using high-resolution array comparative genomic hybridization (CGH), with the aim to identify molecular signatures that delineate malignant from benign NF1 tumors. Experimental Design: We constructed an exon-level resolution microarray encompassing 57 selected genes and profiled DNA from 35 MPNSTs, 16 plexiform, and 8 dermal neurofibromas. Bioinformatic analysis was done on array CGH data to identify concurrent aberrations in malignant tumors. Results: The array CGH profiles of MPNSTs and neurofibromas were markedly different. A number of MPNST-specific alterations were identified, including amplifications of ITGB4, PDGFRA, MET, TP73 , and HGF plus deletions in NF1, HMMR/RHAMM, MMP13, L1CAM2, p16INK4A/CDKN2A , and TP53 . Copy number changes of HMMR/RHAMM, MMP13, p16INK4A/CDKN2A , and ITGB4 were observed in 46%, 43%, 39%, and 32%, respectively of the malignant tumors, implicating these genes in MPNST pathogenesis. Concomitant amplifications of HGF, MET , and PDGFRA genes were also revealed in MPNSTs, suggesting the putative role of p70S6K pathway in NF1 tumor progression. Conclusions: This study highlights the potential of array CGH in identifying novel diagnostic markers for MPNSTs.