A candidate gene approach within the susceptibility region PCaP on 1q42.2-43 excludes deleterious mutations of the PCTA-1 gene to be responsible for hereditary prostate cancer.

OBJECTIVE: The Prostate Carcinoma Tumor Antigen-1 (PCTA-1) is located at the prostate cancer susceptibility locus on chromosome 1q42.2-43 (PCaP). In this candidate gene approach, we searched for deleterious mutations within the PCTA-1 gene and its promoter. MATERIALS AND METHODS: Seventy-seven familial prostate cancer cases from 36 German and French pedigrees were screened for germline mutations in the PCTA-1 gene using enzymatic mutation detection (EMD). Putative missense mutations were genotyped by RPLP and ddNTP primer extension assays in 88 controls to assess allele frequencies and haplotypes. RESULTS: Several sequence variants were found but none of the findings indicated a deleterious mutation. Three affected brothers showed an intronic variation, which may interfere with correct splicing. Four non-conservative SNPs were characterized, coding for the amino acid alterations Y19F, C36R, V56M and S184R. All exchanges were found in controls with common allelic frequencies of at least 28%. Haplotype definition including six SNPs within the PCTA-1 gene revealed a complete linkage disequilibrium. Low haplotype diversity leads to a predominance of only two peptide variants of the PCTA-1 protein, coded by 95% of all chromosomes. CONCLUSIONS: PCTA-1 is not a classical high risk gene with deleterious mutations predisposing to hereditary prostate cancer. Its contribution to prostate cancer susceptibility as a low risk factor in sporadic disease has to be assessed in larger samples by association studies.

Induced micronucleus frequencies in peripheral lymphocytes as a screening test for carriers of a BRCA1 mutation in breast cancer families.

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. It has been suggested that women with breast cancer are deficient in the repair of radiation-induced DNA damage. We have now investigated whether mutagen sensitivity is related to mutations in the breast cancer gene BRCA1. We studied the induction and repair of DNA damage in lymphocytes of women from families with familial breast cancer and breast and ovarian cancer. The mutagens used were gamma-irradiation and hydrogen peroxide and the DNA effects were determined with the micronucleus test and the comet assay. Women with a BRCA1 mutation (n = 12) and relatives without the familial mutation (n = 10) were compared to controls (i.e., healthy women without family history of breast or ovarian cancer; n = 17). Our results indicate a close relationship between the presence of a BRCA1 mutation and sensitivity for the induction of micronuclei. Compared to a concurrent control, 10 of 11 women with a BRCA1 mutation showed elevated radiation sensitivity. Of the 10 related women without the familial mutation, only 2 had clearly enhanced micronucleus frequencies. In addition to the sensitivity toward gamma-irradiation, hypersensitivity toward hydrogen peroxide was also observed, indicating that the mutagen sensitivity is not solely due to a defect in the repair of DNA double strand breaks. In contrast to the results with the micronucleus assay, we found no significant difference between women with and without a BRCA1 mutation with respect to the induction and repair of DNA damage in the comet assay. This finding suggests a normal rate of damage removal and points to a disturbed fidelity of DNA repair as a direct or indirect consequence of a BRCA1 mutation. Our results support the usefulness of induced micronucleus frequencies as a biomarker for cancer predisposition and suggest its application as a screening test for carriers of a BRCA1 mutation in breast cancer families.

Vitamin D receptor polymorphisms as markers in prostate cancer.

Polymorphisms in the vitamin D receptor (VDR) gene have been analyzed in several studies for an association with prostate cancer (PCA) and odds ratios (OR) > or = 3 have been observed in study populations from North America. We studied three polymorphisms in the VDR gene (poly-A microsatellite, TaqI and FokI RFLPs) in 105 controls and 132 sporadic PCA cases from France and in a collection of families from Germany and France. The polymorphisms near the 3' end of the gene were in linkage disequilibrium with an almost complete coincidence of the short poly-A alleles and t (presence of the restriction site) of the TaqI polymorphism, (contingency tables, P<0.0001). An association was found by logistic regression for the poly-A between PCA and the heterozygous genotype (S/L; S < 17, L > or = 17, OR=0.44, 95% confidence interval, CI=0.198-0.966, P=0.041). OR was lower in patients < or = 70 years old and patients with a Gleason score > or = 6. The Tt genotype of the TaqI RFLP also showed an association with PCA (OR=0.5, CI=0.27-0.92, P=0.026). This association was also stronger for patients < or = 70 years old (OR=0.31, CI=0.15-0.63, P=0.001). The risk alleles were S and t alleles as indicated by the OR of the homozygotes, although these were not significant. The FokI RFLP at the 5' end of the gene did not reveal any association (P>0.7). While some association studies differ between Europe and North America, our present findings with the VDR gene agree with those from North America, indicating a weak but general role of the VDR in PCA susceptibility.