Studies of families with breast cancer have indicated that male carriers of BRCA2 mutations are at increased risk of prostate cancer, particularly at an early age. To evaluate the contribution of BRCA2 mutations to early-onset prostate cancer, we screened the complete coding sequence of BRCA2 for germline mutations, in 263 men with diagnoses of prostate cancer who were

Evidence of the existence of major prostate cancer (PC)-susceptibility genes has been provided by multiple segregation analyses. Although genomewide screens have been performed in over a dozen independent studies, few chromosomal regions have been consistently identified as regions of interest. One of the major difficulties is genetic heterogeneity, possibly due to multiple, incompletely penetrant PC-susceptibility genes. In this study, we explored two approaches to overcome this difficulty, in an analysis of a large number of families with PC in the International Consortium for Prostate Cancer Genetics (ICPCG). One approach was to combine linkage data from a total of 1,233 families to increase the statistical power for detecting linkage. Using parametric (dominant and recessive) and nonparametric analyses, we identified five regions with "suggestive" linkage (LOD score >1.86): 5q12, 8p21, 15q11, 17q21, and 22q12. The second approach was to focus on subsets of families that are more likely to segregate highly penetrant mutations, including families with large numbers of affected individuals or early age at diagnosis. Stronger evidence of linkage in several regions was identified, including a "significant" linkage at 22q12, with a LOD score of 3.57, and five suggestive linkages (1q25, 8q13, 13q14, 16p13, and 17q21) in 269 families with at least five affected members. In addition, four additional suggestive linkages (3p24, 5q35, 11q22, and Xq12) were found in 606 families with mean age at diagnosis of < or = 65 years. Although it is difficult to determine the true statistical significance of these findings, a conservative interpretation of these results would be that if major PC-susceptibility genes do exist, they are most likely located in the regions generating suggestive or significant linkage signals in this large study.

Background:The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours.Methods:Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan–Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing.Results:Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P=0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se.Conclusion:BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease.

The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G4A (D1853N), 5558A4T (D1853V), ivs38-8t4c and ivs38-15g4c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17 -3.87, P ¼ 0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C4G variant might be associated with prostate cancer risk. Prostate cancer is the second most common malignancy and the second commonest cause of cancer deaths in men in the European Union, with 143 000 new cases and 60 000 deaths year À1 (GLOB-CAN 2000, www-dep.iarc.fr). The aetiology of prostate cancer is poorly understood. Prostate cancer is known to aggregate in families, indicating that genetic susceptibility may be important, but the genes involved are largely unknown. Linkage studies in multiple case families have suggested susceptibility loci on chromosomes 1q24, 1q42, 1p36, 8p22 -23, 17p, 20q13 and Xq (see recent reviews by DeMarzo et al, 2003;Gronberg, 2003) but none have been definitively replicated. As a consequence of these linkage studies, variants in prostate cancer families have been identified in several genes including Macrophage Scavenger Receptor 1(MSR1), 2 0 -5 0 -oligoadenylate-dependent ribonuclease L (RNASEL) and ELAC2 (chromosome 17p11/HPC2 region) (reviewed in Simard et al, 2003), but again none have been reliably associated with risk.Several independent studies have demonstrated that individuals with germline mutations in BRCA2 are at increased risk of prostate cancer (The Breast Cancer Linkage Consortium, 1999;Edwards et al, 2003;Giusti et al, 2003). There is also some evidence for an increased risk in carriers of BRCA1 mutations (Thompson et al, 2002). More recently, Seppala et al (2003) have found that the CHEK2 variant 1100delC, known to be associated with an increased risk of breast cancer, is also associated with an increased risk of prostate cancer, and Dong et al (2003) found that this and other missense variants in CHEK2 occurred at increased frequency in prostate cancer cases. The proteins encoded by the BRCA1 and BRCA2 genes participate in the maintenance of geno...

The Epstein-Barr virus transcription factor Zta (encoded by BZLF1) is a bZIP protein containing an ␣-helical coiled-coil homodimerization motif (zipper). The Zta zipper forms less-stable dimers than other bZIP proteins, and an adjacent region (CT) interacts with the zipper to form a novel structure that is proposed to strengthen the dimer. Here we question the role of the CT region for Zta function. Cross-linking experiments demonstrate that the entire CT region lies adjacent to the zipper. Detailed analyses of Zta truncation mutations identify an involvement of the proximal CT region (221 to 230) in dimer formation with a further contribution from the distal region (236 to 243). Biophysical analyses reveal that residues 221 to 230 enhance the stability of the coiled coil. The ability of the Zta truncation mutants to interact with three Zta-binding sites also requires the proximal CT region. Fine mapping of DNA-binding requirements highlighted the contribution of these amino acids for Zta function. Thus, the proximal part of the CT region is required to aid the dimerization of Zta and thereby its DNA-binding ability. In contrast, although the distal part of the CT region aids dimerization, it promotes only a modest increase in DNA binding. To probe this further, we defined the contribution from the CT region for Zta to transactivate a promoter embedded within the viral genome. From this we conclude that the proximal part of the CT region is absolutely required, whereas the distal part is dispensable.