分子遺伝学の基礎とその聴神経腫よう研究への応用

Abstract

The basic knowledge of molecular genetics is reviewed briefly, followed by a presentation of the results of an investigation of the vestibular schwannoma using molecular genetic techniques. The NF2 gene, responsible for neurofibromatosis type 2 (NF2), was mapped to the long arm of chromosome 22, and was isolated recently. NF2 is a hereditary disease characterized by bilateral vestibular schwannoma, but chromosome 22 allele loss and NF2 gene mutation are frequently observed not only in NF2 patients but also in non-familial unilateral vestibular schwannomas. In this inves-tigation, chromosome 22 LOH study and NF2 gene mutation analysis were performed in 94 tumor tissues consisting of 91 non-familial unilateral vestibular schwannomas, 2 vestibular schwannomas from NF2 patients, and 1 vagal schwannoma. LOH was stud-ied by using microsatellite markers located in the region of the NF2 gene on chromosome 22. Mutations were screened by SSCP for all 17 exons of the NF2 gene, and samples showing abnormal bands were sequenced by the conventional sequencing system to confirm the presence of mutation. LOH was detected in 35 cases (40%) among 87 cases in which LOH study was possible. Mutation analysis revealed 40 mutations in 36 of 94 tumors (38%). They were detected only in tumor DNA, and not in the constitutional DNA. Detected mutations were all predicted to result in either truncated or abnormal NF2 protein. LOH and/or mutations were detected in 52 cases (55%). These results conform to those of other similar studies, and are compatible with the two hit mutation model of Knudson. This suggests that the NF2 gene acts as a tumor suppressor gene and that its inactivation is an important step in the tumorigenesis of vestibular schwannoma.