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.
Highlights
Neurofibromatosis type 1 (NF1) (MIM 162200) is an autosomal dominant disorder affecting approximately 1 in4,000 people worldwide [1]
Malignant complications are a less frequent but potentially much more serious manifestation of NF1. These often lead to premature death in individuals with NF1 and include malignant peripheral nerve sheath tumors (MPNSTs) which occur in approximately 10% to 15% of patients [3], pheochromocytomas, brain tumors, optic
loss of heterozygosity (LOH) of the NF1 gene was identified in all 10 tumors
Summary
Neurofibromatosis type 1 (NF1) (MIM 162200) is an autosomal dominant disorder affecting approximately 1 in4,000 people worldwide [1]. Neurofibromatosis type 1 (NF1) (MIM 162200) is an autosomal dominant disorder affecting approximately 1 in. Learning difficulties and orthopedic problems occur in up to 50% of individuals with NF1 [2]. Malignant complications are a less frequent but potentially much more serious manifestation of NF1. These often lead to premature death in individuals with NF1 and include malignant peripheral nerve sheath tumors (MPNSTs) which occur in approximately 10% to 15% of patients [3], pheochromocytomas, brain tumors, optic. The NF1 gene, located at 17q11.2, encodes neurofibromin, a 2818 amino acid protein which is expressed at a high level in the brain and central nervous system [4]
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