The neurofibromatosis type 2 gene is mutated in perineurial cell tumors - A molecular genetic study of eight cases

Perineurial cell tumors (PNTs) are rare neoplasms derived from or showing d ifferentiation toward specialized lining cells of the nerve sheath, the per ineurial cells. In this study, we have evaluated neurofibromatosis type 2 ( NF2) gene alterations in eight PNTs using archival formaldehyde-fixed, para ffin-embedded tissue. Two conventional soft-tissue PNTs from the upper back and chest wall, one retiform soft tissue variant from the scapular region, and five sclerosing PNTs from the fingers and palm were studied, All cases showed histological features of PNTs, and the neoplastic cells were positi ve for epithelial mem brane antigen and negative for S100 protein. The codi ng sequences (exons 1 to 15) of the NF2 gene were polymerase chain reaction (PCR) amplified and evaluated for mutations by direct sequencing of the PC R products. Five NF2 point mutations, two in the 5'-untranslated region (UT R) and three in exons 3, 6, and 8, were identified in four of eight cases ( 50%) studied. Exon mutations resulted in changes of predicted amino acids s equences: Asp --> Asn at codon 83, Glu --> Asp at codon 182, and Leu --> Va l at codon 241, In two cases (one with a missense mutation in codon 241), t he same point mutation in the 5'-UTR at the nucleotide position 8958 was id entified. A loss of heterozygosity (LOH) study was pet-formed in three case s. LOH at the NF2 locus was found in one case with a mutation in the 5'-UTR . However, in another case with exon 8 and 5'-UTR mutations, deletion of on e allele of the NF2 gene was previously documented byfluorescence in situ h ybridization. The coexistence of NF2 gene mutations and LOH at the NF2 locu s indicates that the NF2 tumor suppressor gene is altered in PNTs by the tw o-hit mechanism.