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Clinical Cancer Research 14, 1015-1024, February 15, 2008. doi: 10.1158/1078-0432.CCR-07-1305
© 2008 American Association for Cancer Research

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Human Cancer Biology

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

Kiran K. Mantripragada1, Gillian Spurlock1, Lan Kluwe2, Nadia Chuzhanova3, Rosalie E. Ferner4, Ian M. Frayling5, Jan P. Dumanski6, Abhijit Guha7, Victor Mautner2 and Meena Upadhyaya1,5

Authors' Affiliations: 1 Institute of Medical Genetics, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom; 2 Department of Neurosurgery, University Clinic Hamburg-Eppendorf, Hamburg, Germany; 3 Department of Biological Sciences, University of Central Lancashire, Preston, United Kingdom; 4 Department of Clinical Neurosciences, Guy's, King's and St. Thomas' School of Medicine, London Bridge, London, United Kingdom; 5 University Hospital of Wales College of Medicine, Heath Park, Cardiff, United Kingdom; 6 Department of Genetics, University of Alabama at Birmingham, Medical School, Birmingham, Alabama; and 7 The Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Requests for reprints: Kiran K. Mantripragada, Institute of Medical Genetics, Cardiff University, School of Medicine, Heath Park, Cardiff, United Kingdom, CF14 4XN. Phone: 0044-29-20744079; E-mail: kiran.mantripragada{at}gmail.com.

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.







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Molecular Cancer Research Cancer Prevention Research
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Annual Meeting Education Book Cell Growth & Differentiation
Copyright © 2008 by the American Association for Cancer Research.