Another important approach to find prostate cancer susceptibility genes has been to perform association studies in populations of men with and without prostate cancer, typically without regard to family history. These case control studies have been greatly aided by the increased understanding of the variability of the human genome sequence among different individuals and the concept that common diseases may be caused by common genetic variants in the population (65). Thus, by simply examining the frequency of polymorphic alleles, typically single-nucleotide polymorphisms, among cases and controls, associations between genes and disease risk can be rapidly assessed. A large number of genes involved in critical processes that occur in prostate cells, such as androgen action and metabolism, growth factor signaling, carcinogen detoxification, and DNA repair and inflammation, are being systematically evaluated in this fashion. Additionally, genome-wide association studies of prostate cancer involving thousands to millions of genetic markers are being contemplated and initiated (see http://cgems.nci.nih.gov/). These are likely to implicate a large number of genes as affecting prostate cancer risk.
A third approach has been to study the possible roles of genes responsible for other cancer-predisposing syndromes as prostate cancer susceptibility genes. This approach has revealed some interesting leads. The BRCA2 gene has been implicated in early onset prostate cancers (66), and both CHEK2 and NBS1, genes involved in breast cancer susceptibility and the Nijmegen breakage syndrome, have been found to be mutated in prostate cancer families in different study populations (67-69). That these three genes are all involved in DNA repair indicates that defects in the ability to repair damage to DNA and maintain genomic integrity predispose prostate epithelial cells, similar to many other cells in the body, to malignant transformation.
As a result of various epidemiological studies during the past four decades, a link between prostate and breast cancer etiology has been suspected for many years (70-72). However, an examination of a large number of prostate cancer families for other cancers (73) found only tumors of the central nervous system to be in significant excess; the number of breast cancer cases was not significantly elevated. Multiple studies have demonstrated an association between BRCA1 and BRCA2 mutations and increased risk of prostate cancer in mutation carriers (74-77). The most direct evidence for a role of BRCA2 comes from a study by Edwards et al. (66) showing that, in 263 men with diagnoses of prostate cancer who were at most 55 years of age, protein-truncating mutations were found in 2.3% and, notably, all of these mutations were clustered outside the ovarian cancer cluster region. The relative risk of developing prostate cancer by age 56 years from a deleterious germline BRCA2 mutation was 23-fold. This establishes BRCA2 as a bona fide prostate cancer susceptibility gene.
Furthermore, in an extensive study of other cancers in BRCA2 carriers from the Breast Cancer Linkage Consortium (78), a strong association with prostate cancer was seen (estimated relative risk [RR], 4.65; 95% CI, 3.48-6.22) for mutation carriers, particularly for men younger than 65 years of age (RR, 7.33). In support of both these findings, Warner et al. (79) determined the BRCA1 and BRCA2 status of 412 Ashkenazi Jewish women with breast cancer. The cumulative incidence of various cancers was assessed in first-degree relatives. The cumulative incidence of prostate cancer in the first-degree relatives of Ashkenazi Jewish women with breast cancer was 14.8% compared with 3.6% in the first-degree relatives of Ashkenazi Jewish women without breast cancer (p = 0.002). Interestingly, when the affected Ashkenazi Jewish women were divided into mutation carriers and noncarriers, the cumulative incidence rose to 34% in carriers and was 12.6% in noncarriers (p = 0.05). This cannot be caused by recall bias, because the family histories were recorded before the women knew of their mutation status. Although a study of multiplex Ashkenazi Jewish prostate cancer families did not find elevated rates of common mutations in either BRCA1 or BRCA2 (80), this study did not include early onset cases. Overall, although it seems likely that mutations in BRCA1 and BRCA2 increase risk for prostate cancer, particularly in the case of BRCA2 for early onset disease, the contribution of germline mutations in these genes to familial clustering of prostate cancer in general remains to be more fully determined. For example, mutation studies following up from recent linkage studies implicating chromosome 17q12-21 do not suggest that BRCA1 is responsible for the positive LOD scores (81,82). Further studies, most likely involving large combined data sets, will be required to more definitively assess the role of these important breast cancer susceptibility genes in prostate cancer risk.
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