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Identification of 12p as a Region of Frequent Deletion in Advanced Prostate Cancer¹

Departments of Urology [A. S. K., W. B. I., G. S. B.], Pathology [G. S. B.], and Oncology [S. E. K., W. B. I., G. S. B.], The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, and Division of Endocrine Oncology, Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), Academic Hospital Rotterdam, Rotterdam, the Netherlands [M. S.]

The identification of homozygous deletions in malignant tissue has been a powerful tool for the localization of tumor suppressor genes. Representational difference analysis (RDA) uses selective hybridization and the PCR to isolate regions of chromosomal loss and has facilitated the identification of tumor suppressor genes such as BRCA2 and PTEN. Twenty RDA clones were generated by comparing genomic DNA from a prostate cancer xenograft to the same patient's normal kidney DNA. Southern blot analysis of the tester and driver and of normal and xenograft DNA, using the differential products as probes, showed the homozygous deletion in 16 of 20 RDA clones. The sequence of one of the differential products overlapped HSU59962, a genomic GenBank sequence on chromosome 12p12–13. Multiplex PCR of the xenograft DNA using polymorphic repeats mapped the deletion to a 1–5-cM region on 12p. Genomic DNA isolated from a panel of cryostat microdissected metastatic prostate adenocarcinomas/normal pairs was screened for loss of heterozygosity using the same polymorphic repeats. Loss of heterozygosity was demonstrated in 9 (47%) of 19 patients. This region may contain, or lie in close proximity to, tumor suppressor genes important in the progression and/or initiation of prostate cancer.

¹ A. S. K. is an American Foundation of Urologic Disease Scholar. In addition, this work was supported by American Cancer Society Grant 58-005-39-IRG (to A. S. K.); Dutch Cancer Society KWF Grant DDHK 97-1644 (to M. S.); Specialized Programs of Research Excellence Grants CA 62924 (to S. E. K.) and CA 58236 (to W. B. I); and by CaPCURE, National Cancer Institute Grants CA 58236 and CA 59457 (to G. S. B.).

² To whom requests for reprints should be addressed, at The Johns Hopkins Hospital, James Buchanan Brady Urological Institute, Marburg 105, 600 North Wolfe Street, Baltimore, MD 21287-2101.

Received 7/29/98. Accepted 10/27/98.

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