Objective: Neurofibromatosis type 1 (NF1) patients have a 13% risk of developing a malignant peripheral nerve sheath tumor (MPNST). Many MPNSTs are histopathologically complex, with regions exhibiting features of the original benign plexiform neurofibroma (PNF), of an atypical PNF, or of MPNST showing varying degrees of de-differentiation. This study analyzed the genetic alterations associated with this pathological heterogeneity in order to identify the genetic processes involved in transformation from a benign to an aggressive malignant tumor.

Methods: A histological and molecular analysis of a single MPNST tumor that was subdivided into three histopathologically distinct regions, a benign PNF (region 1), an atypical PNF (region 2), and a high-grade MPNST (region 3), was carried out. Tumor DNA from each region was analyzed in conjunction with the patient's lymphocyte DNA. Somatic mutation analyses included loss-of heterozygosity (LOH), MLPA analysis, NF1 gene sequencing, and a microarray comparative genomic hybridisation (array CGH) analysis.

Results: The patient had a germline NF1 splice-site mutation. The NF1-associated LOH analysis found that LOH increased in the three tumor areas, with 9, 42, and 97% LOH evident in regions 1, 2, and 3, respectively. Additional genetic changes, including losses of TP53, RB1, CDKN2A, and of several oncogenes and cell-cycle genes, were found only in the malignant MPNST (region 3). Array CGH also identified genomic gains and losses in DNA from region 3.

Discussion: This is the first study that correlates the histological and molecular changes associated with MPNST development, confirming the significant cellular and genetic heterogeneity that poses both diagnostic and therapeutic challenges.