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Somatic Mutations of the von Hippel-Lindau Tumor Suppressor Gene and Loss of Heterozygosity on Chromosome 3p in Human Glial Tumors¹

Departments of Neurosurgery [H.K., I.Y., S.I., M.S.] and Urology [K.K., M.Yo., M.Ya.], Yokohama City University School of Medicine, 3-9 Fukuura Kanazawa-ku, Yokohama 236, and Department of Urology, Kochi Medical School, Kohasu, Okoh-cho, Nangoku-shi 783 [T.S.], Japan

Molecular genetic analysis of von Hippel-Lindau tumor suppressor gene (VHL gene) was performed on 38 tissues of human glial tumors (ependymoma, 1; astrocytoma, 6; oligodendroglioma, 1; oligoastrocytoma, 2; anaplastic oligoastrocytoma, 3; anaplastic astrocytoma, 14; glioblastoma multiforme, 11). Somatic DNAs extracted from frozen tumor specimens were examined by single-strand conformational polymorphism analysis and direct sequencing. In addition, loss of heterozygosity (LOH) on chromosome 3p in 15 glial tumor cases, lymphocyte DNAs of which were available, was examined by use of 10 microsatellite probes and two polymorphism markers for the VHL gene. Two cases of low-grade gliomas showed somatic sense mutations in exon 3 of the VHL gene, and 6 of 15 cases (40.0%) showed LOH of chromsome 3p. The VHL gene-mutated cases also showed LOH. The retention of heterozygosity and high pathological grade of glial tumors were correlated significantly. In addition, Kaplan-Meier survival analysis for patients with glial tumors showed that patients with LOH had a significantly longer survival time than those without LOH. These results suggest that somatic mutations on 3p, including the VHL gene, may be involved in tumorigenesis of some low-grade glial tumors.

¹ This work was supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed. Phone: 81-45-787-2663; Fax: 81-45-783-6121.

Received 11/26/96. Accepted 1/27/97.

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