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Defects of DNA Mismatch Repair in Human Prostate Cancer¹

Laboratory of Cancer Genomics, Hollings Cancer Center [Y. C., D. K. W., C. W. S.], and Departments of Pathology [M. M. F., J. M., D. K. W.] and Urology [J. W., W. R. T., N. K. B.], Medical University of South Carolina, Charleston, South Carolina 29425, and Department of Urology, Second Affiliated Hospital of Kunming Medical College, Kunming 650101, China [J. W.]

Loss of mismatch repair (MMR) function leads to the accumulation of errors that normally occur during DNA replication, resulting in genetic instability. Germ-line mutations of MMR genes in the patients with hereditary nonpolyposis colorectal cancer lead to inactivation of MMR protein functions, and the defects of MMR are well correlated to the high rate of microsatellite instability in their tumors. Previous studies (T. Uchida, et al. Oncogene, 10: 1019–1022, 1995; S. Egawa, et al. Cancer Res., 55: 2418–2421, 1995; J. M. Cunningham, et al. Cancer Res., 56: 4475–4482, 1996; X. Gao, et al. Oncogene, 9: 2999–3003, 1994; H. Rohrbach, et al. Prostate, 40: 20–27, 1999) have shown that genetic instability (chromosomal and microsatellite instability) is detectable in human prostate cancer. To elucidate the role of MMR genes in the tumorigenesis of prostate cancer, we evaluated the expression of these genes in human cancer cell lines and in tumor specimens. Using Western blot analysis, we detected loss among MSH2, MLH1, PMS2, and PMS1 proteins in DU145, LNCaP, p69SV40T, M2182, and M12 cells. In addition, genomic instability in the prostate cell lines including DU145, PC3, LNCaP, p67SV40T, M2182, and M12 was detected by a microsatellite mutation assay. Significantly, immunohistochemical analysis of prostatic tissue revealed the reduction or absence of MMR protein expression in the epithelium of prostate tumor foci compared with normal adjacent prostate tissue. In contrast to hereditary nonpolyposis colorectal cancer, characterized by defects predominantly in MLH1 and MSH2, the samples we examined showed more tumor foci with loss of PMS1 and PMS2. PMS1, which is only expressed in the basal cells in normal glands, is conspicuously absent in most prostate cancer. From these results, we conclude that there are defects of MMR genes in human prostate cancer.

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