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Loss of Heterozygosity and Somatic Mutations of the VHL Tumor Suppressor Gene in Sporadic Cerebellar Hemangioblastomas¹

Department of Pathology, Catholic University Medical College, Seoul, Korea [J-Y. L., S-M. D., W-S. P., N-J. Y., C-S. K.]; Department of Pathology, Seoul National University Medical College, Seoul, Korea [J-J. J., J-G. C.]; Laboratory of Immunobiology, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland [B. Z.]; and Laboratory of Pathology [W-S. P., I. A. L., A. O. V., Z. Z.] and Urologic Oncology Branch [W. M. L.], National Cancer Institute, Bethesda, Maryland 20892

Cerebellar hemangioblastoma is a benign central nervous system neoplasm with characteristic proliferation of vascular and stromal cells. There is increasing evidence that the stromal cell population may represent the neoplastic component of hemangioblastoma, whereas the vascular component may be composed of reactive, nonneoplastic cells. Therefore, successful genetic testing for loss of heterozygosity requires selective analysis of target cell populations.

Here, tissue microdissection was used to selectively analyze the stromal cell component of 20 archival sporadic cerebellar hemangioblastomas for loss of heterozygosity at the Von-Hippel Lindau (VHL) gene and somatic VHL gene mutations. Allelic deletions at the VHL gene locus were detected in the stromal cell component with one or more markers (D3S1038, D3S1110, and/or 104/105) in 10 of 19 (52.6%) informative cases. In all cases, heterozygosity at the VHL gene locus was retained in the vascular component. In two cases, aberrant bands in exon 2 of the VHL gene were demonstrated in the stromal cells by PCR-based single-strand conformation polymorphism analysis, and somatic missense mutations were successfully characterized in two of the sporadic hemangioblastomas by direct sequencing.

The results suggest that allelic losses and mutations of the VHL tumor suppressor gene play a role in sporadic cerebellar hemangioblastoma tumorigenesis. Furthermore, because the genetic changes were detected in selectively procured stromal cell areas, the data provide strong evidence that the stromal cell represents a neoplastic component of hemangioblastoma.

¹ This work was supported in part by the Catholic Medical Center Research Fund for Special Projects.

² To whom requests for reprints should be addressed, at Laboratory of Pathology, National Cancer Institute, NIH, Building 10, Room 2N212, 9000 Rockville Pike, Bethesda, MD 20892.

Received 8/ 1/97. Accepted 12/ 3/97.

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