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Open Access Primary research

Molecular heterogeneity in malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1

Laura Thomas1, Victor-Felix Mautner2, David N Cooper1 and Meena Upadhyaya1*

Author Affiliations

1 Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK

2 Department of Maxillofacial Surgery, University Medical Centre Hamburg-Eppendorf, Hamburg, D-20246, Germany

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Human Genomics 2012, 6:18  doi:10.1186/1479-7364-6-18

Published: 4 September 2012

Abstract

Neurofibromatosis type-1 (NF1), resulting from NF1 gene loss of function, is characterized by an increased risk of developing benign and malignant peripheral nerve sheath tumors (MPNSTs). Whereas the cellular heterogeneity of NF1-associated tumors has been well studied, the molecular heterogeneity of MPNSTs is still poorly understood. Mutational heterogeneity within these malignant tumors greatly complicates the study of the underlying mechanisms of tumorigenesis. We have explored this molecular heterogeneity by performing loss of heterozygosity (LOH) analysis of the NF1, TP53, RB1, PTEN, and CDKN2A genes on sections of 10 MPNSTs derived from 10 unrelated NF1 patients. LOH data for the TP53 gene was found to correlate with the results of p53 immunohistochemical analysis in the same tumor sections. Further, approximately 70% of MPNSTs were found to display intra-tumoral molecular heterogeneity as evidenced by differences in the level of LOH between different sections of the same tumor samples. This study constitutes the first systematic analysis of molecular heterogeneity within MPNSTs derived from NF1 patients. Appreciation of the existence of molecular heterogeneity in NF1-associated tumors is important not only for optimizing somatic mutation detection, but also for understanding the mechanisms of NF1 tumorigenesis, a prerequisite for the development of specifically targeted cancer therapeutics.

Keywords:
Neurofibromatosis type 1; Malignant peripheral nerve sheath tumors; Molecular heterogeneity; TP53