Prostate Cancer Linkage Studies
Hereditary Prostate Cancer 1
Prostate Cancer Predisposing Locus
Hereditary Prostate Cancer X
CAPB
ELAC2/HPC2
HPC20
8p Loci
8q
BRCA1 and BRCA2
KLF6
AMACR
Other Potential Prostate Cancer Genes
Other Regions Identified by Linkage Studies
Genome-wide Association Studies

Like most cancers, prostate cancer is a complex neoplastic disorder in which disease initiation is the result of an interaction between genetic and nongenetic factors. The identification of causative genes for prostate cancer, however, has been elusive in spite of segregation analyses of prostate cancer families that support the existence of one or more hereditary prostate cancer genes.[1-8] Several candidate loci have been identified by performing genome-wide linkage analysis studies in high-risk families, but confirmation of these proposed susceptibility loci from subsequent studies has often been lacking. Further, some prostate cancer susceptibility genes have been characterized by positional cloning, but follow-up studies have not yet demonstrated that any of these loci contribute to a significant number of high-risk prostate cancer families. While the goal of linkage analysis is to identify the chromosomal location of prostate cancer susceptibility genes, none of the putative genes in these regions identified to date have been widely accepted as clinically useful. Examples of loci that have been identified in studies of high-risk families are discussed below and are summarized in Table 2.

The recognition that prostate cancer clusters within families has led many investigators to collect multiplex families with the goal of localizing prostate cancer susceptibility genes through linkage studies. Despite the extensive collection of prostate cancer families and the formation of a collaborative research group (the International Consortium for Prostate Cancer Genetics [ICPCG]), the identification of prostate cancer genes has been exceedingly difficult. A review of eight prostate cancer linkage studies that evaluated a total of 4,600 cases of prostate cancer from 1,293 kindreds found several methodological differences. The authors suggest that differences in populations, enrollment criteria, and underlying genetic models used for each analysis may account for the lack of consistency between linkage studies.[9] The following discussion highlights both the clinical and research issues leading to this complexity.

Linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals, and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. The statistical power of linkage analysis is affected by:

• Family size and having a sufficient number of family members who volunteer to contribute DNA.
• The number of disease cases in each family.
• Factors related to age at disease onset.
• Gender differences in disease risk.

Because the risk of prostate cancer is influenced by both age at onset in affected relatives and number of relatives affected, the lack of accurate family history information about prostate cancer can limit the overall analysis.

Because a standard definition of hereditary prostate cancer (HPC) has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[9] One criterion that has been proposed is the Hopkins Criteria that provides a working definition of HPC families.[10] The three criteria are kindreds with prostate cancer in the following:

1. Three or more first-degree relatives (father, brother, son),
2. Three successive generations of either the maternal or paternal lineages, and/or
3. At least two relatives affected at age 55 years or younger.

Families need to fulfill only one of these criteria to be considered to have HPC. Validity of these research criteria has not been confirmed for clinical management and must await identification of specific prostate cancer susceptibility genes. Using these criteria, a study has shown that approximately 5% of men in a large surgical series will be from a family with HPC.[10]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. As a man’s lifetime risk of prostate cancer is 1 in 6, it is possible that families under study have men with both inherited and sporadic prostate cancer.[11] Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. Currently there are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease. Similarly, there are no definitive data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum screening as the rates of prostate cancer in families will differ between screened and unscreened families.

In an effort to clarify the inconsistent linkage results, the ICPCG combined genome-wide linkage data from 1,233 families contributed by ten individual research teams. One analytic approach used the entire set of 1,233 families and five regions of suggestive linkage (logarithm of the odd [LOD] scores between 1.87 and 3.30) were identified: 5q12, 8p21, 15q11, 17q21, and 22q12. Therefore, the pooled analysis did not formally confirm any previously identified chromosomal regions of interest (see below). In the hope that targeting more homogenous family subsets might facilitate gene identification, a second analysis focused on subsets of the 1,233 families sharing common features, such as multiple affected family members or younger age at diagnosis. In 269 families with at least five affected members, significant linkage was detected at 22q12 (LOD score 3.57) and suggestive linkage was also observed at 1q25, 8q13, 13q14, 16p13, and 17q21. In 606 families with members aged 65 years or younger at diagnosis, linkage was suggested at 3p24, 5q35, 11q22, and Xq12.[12] These findings may facilitate prioritization of genomic regions for further study.

One way to address the inconsistency between linkage studies is to require inclusion criteria that defines clinically significant disease (e.g., Gleason grade ≥7, PSA ≥20 ng/mL) in an affected man.[13-15] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[16,17] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[18,19]

The results of a genome-wide scan of 91 high-risk prostate cancer families meeting the Hopkins criteria from the United States and Sweden suggested the presence of a major prostate cancer susceptibility locus at chromosome 1q24,[20] designated HPC1. Assuming genetic heterogeneity (i.e., that it is likely that only a subset of these 91 families carry an HPC1 mutation), the odds favoring the presence of this gene are nearly 1 million to 1. The genetic evidence supporting the existence of HPC1 was confined to 35% of the 91 families. This subgroup was characterized clinically by having more than five affected family members and an average age at prostate cancer diagnosis younger than 65 years. Further analyses of families that are genetically linked to HPC1 revealed the following characteristics:

• Younger age at diagnosis.
• Higher tumor grade (Gleason score).
• More advanced stage at diagnosis.[21,22]

Despite the strength of the initial results,[20] subsequent studies have often failed to confirm the linkage.[23-26] Nevertheless, confirmatory results were obtained in two studies in the United States that involved 59 and 92 families.[27,28] Linkage evidence in these reports was stronger among families in which prostate cancer was diagnosed earlier in life (<67 years) or that fit the Hopkins definition of HPC. In an analysis of 41 families from Utah, in which the mean number of affected men per family was large (10.7), linkage with 1q24-25 was confirmed.[29] The ICPCG pooled data from 772 families in North America, Australia, Finland, Norway, Sweden, and the United Kingdom, and obtained some evidence of linkage at 1q24.[30] The estimated percentage of familial prostate cancer families explained on the basis of this putative gene locus was 6%. Stronger evidence of linkage was seen among families with a male-to-male pattern of inheritance. Modest evidence for linkage to this region was also identified on a genome-wide scan of 188 families from Johns Hopkins,[31] including 51 kindreds examined in the initial positive linkage study.[20] A study of 33 African American families demonstrated some evidence in support of prostate cancer linkage to markers that map to several HPC candidate regions.[32]

Data suggest that the RNASEL gene at 1q25 may be the molecular basis of the prostate cancer susceptibility locus HPC1. The gene encodes an endoribonuclease that is a member of the interferon-regulated 2-5A system. Deleterious germline RNASEL mutations were detected in two out of eight families with prostate cancer linkage to 1q24-25 markers. Follow-up studies by several groups, however, have not identified a significant number of RNASEL germline variants among families with HPC.[33,34] In a study of Finnish men with prostate cancer, a stop mutation, E265X, was found in 4.3% of the men from HPC families compared with 1.8% of controls.[35] A founder frameshift mutation in RNASEL (471delAAAG) was identified in 4% of Ashkenazi individuals.[36] The frequency of this mutation was higher in men with prostate cancer than in elderly male controls (6.9% vs. 2.4%, odds ratio [OR] = 3.9; 95% confidence interval [CI], 0.6–15.3; P = .17). Significant associations were noted between the common RNASEL polymorphism R462Q and familial prostate cancer.[33] This substitution results in a threefold reduction in RNASEL activity.[37] A Swedish population-based case-control study examined the prevalence of E265X and other variants in the RNASEL gene. There were no differences for the E265X truncating mutation between the 780 controls (1.9%), 1,204 sporadic prostate cancer cases (1.9%), or 350 familial/HPC prostate cancer cases (1.4%).[38] Further, this group did not find significant differences between cases and controls for the R462Q variant. A meta-analysis summarized the data from ten case-control studies that contained data on the RNASEL variants E265X, R462Q and D541E. Only the D541E allele was associated with an increased risk of prostate cancer, although the magnitude of the effect was small.[39] In summary, there is evidence both for and against rare and common RNASEL variants contributing to a proportion of familial prostate cancer cases, though larger studies are required to more carefully delineate both the clinical and biologic implications of germline RNASEL variants.

A genome-wide scan using 49 high-risk prostate cancer families of German and French origin resulted in evidence of a prostate cancer predisposition locus on chromosome 1q42.[24] This is believed to be a separate gene from the HPC1 locus at 1q24.[20] Prostate cancer linkage to this locus, which has been designated PCAP, was described in a second set of European prostate cancer families [40] and families with evidence of linkage had an earlier average age at diagnosis (<65 years). PCAP linkage has not been observed in several studies of U.S. and international HPC families.[9,17,31,41-48]

A prostate cancer susceptibility locus (designated HPCX) has been mapped to the X chromosome by using a set of high-risk prostate cancer families from the United States, Finland, and Sweden.[49] In this initial report, linkage to a hypothesized gene located at Xq27-28 was predicted to account for 16% of prostate cancer among the 360 families that were analyzed. Analytic epidemiology studies have shown a higher relative risk (RR) of prostate cancer among men with an affected brother versus men with an affected father, a finding that supports the possibility of a prostate cancer susceptibility locus on the X chromosome;[50] however, this pattern is also consistent with an autosomal recessive mode of inheritance or environmental factors. Follow-up HPCX linkage studies have shown some evidence in support of the existence of this locus,[44,51-53] and an ICPCG meta-analysis is in process. Using linkage disequilibrium analysis, a specific haplotype in the Xq27-28 region of HPCX was found to be significantly associated with X-linked prostate cancer in Finnish families.[54] This finding was confirmed in a case control training set (292 cases and controls) and replicated in independent test subjects (215 cases and controls). The Xq27 haplotype extended from rs5907859 to rs1493189, and was associated with prostate cancer (OR = 3.41; 95% CI, 1.04–11.17; P = 0.034).[55]

Many cancer susceptibility genes increase the risk for more than one type of malignancy. For example, BRCA1 mutations increase a woman’s chance of developing both breast and ovarian cancer. In this regard, a set of prostate cancer families who have one or more cases of primary brain cancer was identified.[56] In this set of 12 families, prostate cancer linkage to 1p36 markers was observed. This hypothetical gene locus has been named CAPB. Loss of heterozygosity (LOH) of this same genetic region was previously observed in sporadic brain cancers, suggesting that there is a tumor suppressor gene in this genomic interval. Other groups have not consistently confirmed prostate cancer linkage to CAPB in families with both brain and prostate cancers.[42,57] Further, there is evidence for linkage to 1p36 in one study of 207 prostate cancer families, considering as affected only those individuals with prostate cancer. This was particularly evident in families with early-onset disease in which the prostate cancer was diagnosed before age 59 years.[57] This raises the possibility that CAPB mutations may contribute to prostate cancer in a site-specific manner.

The ELAC2/HPC2 prostate cancer predisposition gene on chromosome 17p was cloned after a genome-wide scan of high-risk families from Utah (Table 3).[58] Two segregating germline mutations were identified among these multiplex prostate cancer families. Neither linkage evidence to 17p11 markers nor rare ELAC2/HPC2 variants were found in other sets of multiplex families.[59] The ELAC2/HPC2 gene from 300 men from 150 prostate cancer families (with three or more cases of prostate cancer) was sequenced and identified only one stop codon and five additional missense mutations.[60]

Two common variants in ELAC2/HPC2 have been extensively studied for their potential contribution to prostate cancer susceptibility. In a clinic-based study of 350 prostate cancer cases and 266 age-matched and race-matched controls, it was reported that men who carry both of two common polymorphisms in the ELAC2/HPC2 gene experience a modest increase in risk of prostate cancer (OR = 2.4; 95% CI, 1.1–5.3).[61] Many additional studies have been reported, six of which have been pooled in a meta-analysis.[62] The authors suggest that the use of unscreened controls in case-control studies results in the inclusion of a significant number of men with prostate cancer cases among subjects who are classified as controls. This misclassification error will bias association studies toward the null. In the ELAC2/HPC2 meta-analysis, if exclusion of data from association studies in which prostate cancer screening was performed in controls resulted in a positive association between the Thr541 substitution and prostate cancer risk (OR = 1.8; 95% CI, 1.2–2.7; P = .0029), then to the extent that misclassification bias is operating in this series, the reported OR may underestimate the strength of the observed association. Studies using population-based sampling might be expected to clarify the potential role of common ELAC2/HPC2 polymorphisms in prostate cancer. An Australian study found no significant association between ELAC2/HPC2 and prostate cancer.[63] Furthermore, these authors pooled their new data with those from seven published studies; their meta-analysis strengthened the conclusion that no association exists.

Evidence for yet another prostate cancer susceptibility locus on chromosome 20, which has been termed HPC20, has been reported.[44,64] In stratified analyses, the group of patients with the strongest evidence of linkage to this locus were the families with fewer than five family members affected with prostate cancer, a later average age at diagnosis, and no male-to-male transmission, a pattern distinctly different from that reported for HPC1. Some evidence of prostate cancer linkage to HPC20 has been observed in two independent sets of families,[65,66] though the candidate genomic interval remains large; however, a combined linkage analysis of 1,234 pedigrees performed by the ICPCG failed to replicate linkage of hereditary prostate cancer to 20q13 markers.[67] In this report, the original 158 Mayo families that were used to identify HPC20 had a maximum heterogeneity LOD score under a recessive model of 2.78 whereas the remaining 1,076 families has a maximum heterogeneity LOD score of 0.06 using the same model. These data suggest that if HPC20 truly exists, it may only account for a small fraction of all hereditary prostate cancers.

Chromosome 8p is commonly deleted in prostate cancer; consequently, many groups have focused on using deletion mapping in an attempt to localize one or more tumor suppressor genes in this region. Several genome-wide scans have provided modest evidence of prostate cancer linkage to markers that map to 8p.[31,45,68] Evidence has been reported that both rare and common variants in the macrophage scavenger receptor 1 gene (MSR1) at 8p22 are associated with prostate cancer susceptibility (Table 3).[69,70] Case-control studies examining an association between these alleles and prostate cancer, however, did not show significant findings, including a meta-analysis.[71-74] Germline variants of the LZTS1 gene, also at 8p22, have been reported to be associated with sporadic prostate cancer.[75]

A combined analysis of somatic deletions of chromosome 8p in prostate cancer tumor tissue and fine-mapping linkage in multiple-case families has identified two additional regions (8p23.1 and 8p21.3) that are associated with prostate cancer risk.[76]

A linkage peak at chromosome 8q24 was reported in 323 Icelandic prostate cancer families with a peak LOD score of 2.11. Detailed genotyping of this region revealed an association in three case-control populations in Sweden, Iceland, and the United States with allele -8 at marker DG8S737. The population attributable risk for prostate cancer from this allele was 8%. The results were replicated in an African American case-control population, in which the population attributable risk was 16%.[77] Support for the existence of a prostate cancer susceptibility gene at 8q24, specifically in African American men, was also observed using admixture mapping.[78]

A series of studies confirming the association between prostate cancer risk and single nucleotide polymorphism (SNP) rs1447295 has been published.[79-85] Three additional studies evaluating the 8q24 locus have identified a second SNP, rs6983267, which is close to but distinct from rs1447295.[82,86,87] Furthermore, a multiethnic analysis identified five new variants all within this same region, each of which appears to be independently associated with prostate cancer risk. A number of these variants are much more common than rs1447295, suggesting that the proportion of all prostate cancers that may be explained on the basis of genetic variation in this region could be quite large. The well-known differences in prostate cancer risk among diverse population groups also may be related to these findings.[87,88] A meta-analysis, including data from ten independent studies, has demonstrated a statistically significant association for four 8q24 variants in prostate cancer risk.[89] These observations are also notable because they occur in a region without known protein-encoding genes, which makes it very difficult to know what the underlying biological mechanism of susceptibility is likely to be. This is likely a recurring situation with genome-wide association studies in which statistically convincing associations are detected, but the truly causal variant and biological mechanism will be difficult to determine, requiring biochemical and other functional studies. C-MYC is the closest cancer-related gene to the 8q candidate region. At least one study has demonstrated an association between a SNP in the first intron of c-MYC and prostate cancer raising the possibility that the c-MYC gene is associated with the overall 8q association findings.[85] These susceptibility alleles are generally associated with OR of 2 or lower and are not immediately clinically relevant.

Refer to the Polymorphisms and Prostate Cancer Susceptibility section of this summary for more information on polygenic factors in 8q.

Chromosome 8q24 risk variants have also been characterized in families with HPC. Twelve 8q24 variants from Regions 1, 2, and 3 and one variant from the c-MYC gene were genotyped in 168 probands from HPC families: 1,404 prostate cancer patients from non-HPC families undergoing radical prostatectomy, and 560 control subjects undergoing prostate cancer screening at Johns Hopkins University.[90] Risk alleles from five SNPs in Region 1 (rs1447295, rs4242382, rs7017300, rs10090154, and rs7837688) and alleles from two SNPs in Region 2 (rs6983561 and rs16901979) were significantly more frequent in HPC probands compared with controls. Genotype risk for HPC was also higher for these seven SNPs. Family-based transmission tests found that risk alleles of two SNPs in Region 2 were significantly over-transmitted to affected men in these HPC families. No evidence for linkage to 8q24 was found in these HPC families. Another report from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) evaluated five SNPs and one microsatellite marker found previously to be associated with prostate cancer in 403 non-Hispanic white families with discordant sibling pairs.[91] Using a family-based association test, the minor allele of rs6983561 and the major allele of rs6983267 were found to be preferentially transmitted to affected men. Furthermore, rs6983561 was significantly associated with prostate cancer among men diagnosed before age 50 years and rs6983267 was significantly associated with clinically aggressive disease. These data provide further support for modification of familial prostate cancer risk by variants in 8q24, particularly variants from Region 2.

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate cancer–affected individuals. Conflicting evidence exists regarding the linkage to some of the loci listed above. Data are also limited on the proposed phenotype associated with each loci, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Studies of male BRCA1 [92] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer, as well as other cancers.[93]

Among male BRCA1 mutation carriers from hereditary breast ovarian cancer kindreds studied by the Breast Cancer Linkage Consortium (BCLC) family set, the risk of prostate cancer was not elevated overall (RR = 1.1; 95% CI, 0.8–1.5); however, the risk was modestly increased (RR = 1.8; 95% CI, 1.0–3.3) among men younger than 65 years.[92]

In contrast, a similar study of male BRCA2 mutation carriers in hereditary breast ovarian cancer kindreds from the BCLC demonstrated that the risk of prostate cancer associated with BRCA2 mutations was increased overall (RR = 4.7; 95% CI, 3.5–6.2). The incidence was also markedly increased among men younger than 65 years at diagnosis (RR = 7.3; 95% CI, 4.7–11.5).[94] Another report from the BCLC suggests that prostate cancer risk may be lower among men with a mutation in the central region of the BRCA2 gene, known as the ovarian cancer cluster region (RR = 0.5; 95% CI, 0.2–1.0).[95]

Several small case series in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi men with prostate cancer.[96-98] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of Ashkenazi (Eastern European) Jewish ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.7%–1.1%) for the 185delAG mutation, 0.3% (95% CI, 0.2%–0.4%) for the 5382insC mutation, and 1.3% (95% CI, 1.0%–1.5%) for the BRCA2 6174delT mutation.[99-102] (Refer to the Major Genes section of the PDQ summary on Genetics of Breast and Ovarian Cancer for more information on the BRCA1 and BRCA2 genes.) In these studies, the point estimates of risk were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In a study of more than 5,000 American Ashkenazi Jewish volunteers from the Washington D.C. area (the Washington Ashkenazi Study [WAS]), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among men who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4%–30%) compared with 3.8% among noncarriers (95% CI, 3.3%–4.4%).[102] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by the age of 70 years; 95% CI, 6%–28%). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

Two studies using similar methods examined the prevalence of Ashkenazi founder mutations among Jewish men with prostate cancer and found an overall positive association between founder mutation status and prostate cancer risk. The first study [103] analyzed 979 consecutive Ashkenazi men with prostate cancer diagnosed in a large region of Israel, and compared the prevalence of founder mutations with age-matched controls from two different sources, the WAS and the Molecular Epidemiology of Colorectal Cancer (MECC) study from Israel. Overall, there was a twofold, statistically significant increase in the risk of prostate cancer among all carriers of founder mutations (OR = 2.1; 95% CI, 1.2–3.6). The magnitude of this risk was similar for BRCA1 and BRCA2 founder mutations, but only the BRCA2 association was statistically significant, when considered separately. This study did not find that mutation carriers developed prostate cancer at an earlier-than-usual age. Further, there was no evidence of unique or specific histopathology findings within the mutation-associated prostate cancers.

The second study [104] tested genomic DNA from 251 Ashkenazi men diagnosed with prostate cancer at their institution for the three common BRCA1/2 founder mutations. Using the control data from the WAS study described above, and after adjusting for age, all founder mutation carriers had a significantly increased risk of prostate cancer (OR = 3.4; 95% CI, 1.6–7.1). When evaluating BRCA1 versus BRCA2 founder mutations separately, no significantly increased risk of prostate cancer was detected for BRCA1 mutation carriers, while the risk among BRCA2 mutation carriers was increased substantially (OR = 4.8; 95% CI, 1.9–12.2).

These two studies support the hypothesis that prostate cancer occurs excessively among carriers of Ashkenazi Jewish founder mutations, and both suggest that the risk may be greater among men with the BRCA2 founder mutation (6174delT) than those with one of the BRCA1 founder mutations (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differ somewhat, undoubtedly because of interstudy differences related to participant ascertainment, calendar time differences in diagnosis, and analytic methods.

Two hundred sixty-three men with prostate cancer diagnosed in the United Kingdom (U.K.) before the age of 56 years underwent testing for BRCA2 mutations.[105] Screening of all coding regions resulted in the identification of six men (2.3%) with protein-truncating BRCA2 mutations, as well as an additional 22 men harboring variants of undetermined significance. Three of the men with deleterious mutations had no family history of prostate, breast, or ovarian cancer. Using estimates of the frequency of BRCA2 mutations in the general U.K. population of 0.14% and 0.12%, the investigators estimated a 23-fold RR of early-onset prostate cancer attributable to BRCA2 mutations (95% CI, 9–57). In a similar study conducted in a U.S. population,[106] 290 men (11% African American and 87% Caucasian) diagnosed with prostate cancer prior to age 55 years, unselected for family history, were screened for BRCA2 mutations. Two protein-truncating BRCA2 mutations were identified for a prevalence of 0.69% (95%CI, 0.08–2.49%). Both mutations were found in Caucasian cases for a prevalence in Caucasians of 0.78% (95%CI, 0.09–2.81%) and a 7.8 (95%CI, 1.8–9.4) RR of prostate cancer in Caucasian BRCA2 mutation carriers. Of the two individuals with a protein truncating mutation, neither reported a family history of breast or ovarian cancer.[106] This study confirms that on rare occasions germline mutations in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the U.S.

A founder mutation in BRCA2 (999del5 in exon 9), which was originally described in male and female breast cancer families in Iceland, has been reported to be associated with aggressive prostate cancer in multiple small studies.[107-112] A recent population-based case-control study between BRCA2 999del5 mutation carriers and noncarriers (all of whom had a prostate cancer diagnosis) from the Icelandic Cancer Registry was conducted.[113] Five hundred and twenty-seven out of 596 prostate cancer patients from Iceland with prostate tissues available for pathology review had genetic analysis performed. Thirty patients carrying this BRCA2 mutation were identified and matched to 59 noncarriers by year of diagnosis and year of birth. The results showed that mutation carriers had lower mean age of prostate cancer diagnosis, advanced tumor stage, higher tumor grade, and shorter median survival than noncarriers. Carrying the BRCA2 999del5 mutation was associated with a higher risk of death from prostate cancer (hazard ratio [HR] = 3.42; 95% CI, 2.12–5.51) which remained after adjustment for stage and grade (HR = 2.35; 95% CI, 1.08–5.11). These investigators concluded that the Icelandic BRCA2 999del5 founder mutation was associated with aggressive prostate cancer. Their observations differ from similar analyses of BRCA-related prostate cancer in other population groups and may be specific for the Icelandic founder mutation.

Genomic DNA of 266 subjects from 194 HPC families was screened for BRCA2 mutations using sequence analysis focusing on exonic and preserved regulatory regions. Although a number (n = 31) of nonsynonymous variations were identified, no truncating or deleterious mutations were detected. These investigators concluded that BRCA2 mutations did not significantly contribute to hereditary prostate cancer.[114] A genome-wide scan for HPC using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence for linkage to chromosome 17q markers.[46] The maximum LOD score in all families was 2.36, and the LOD score increased to 3.27 when only those families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[115] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancer was found to have a truncating mutation (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence for a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17-linked families.

In another study from the UM-PCGP, common genetic variation in BRCA1 was examined.[116] Conditional logistic regression analysis and family-based association tests were performed in 323 familial and early-onset families, which included 817 men with and without prostate cancer to investigate the association of SNPs tagging common haplotype variation in a 200-kb region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (OR = 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[46] These findings support further investigation of BRCA1 variants in prostate cancer risk.

In an effort to clarify the relationship between BRCA1/BRCA2 and prostate cancer risk, 215 BRCA1-positive and 188 BRCA2-positive families were studied. One hundred fifty-eight of these men were diagnosed with prostate cancer, eight of whom were known to carry their family’s BRCA1 mutation, and 20 who were known to carry a BRCA2 mutation. Archival pathology material (paraffin blocks) was retrievable from four men with a BRCA1 mutation and 14 men with a BRCA2 mutation. LOH was observed at the BRCA2 locus in 10 of 14 BRCA2-related prostate cancers versus 0 of 4 BRCA1-related prostate cancers (P = 0.02). BRCA2 mutation carriers were estimated to have a 3.5-fold increased prostate cancer risk, while BRCA1 mutation carriers did not appear to be at increased risk. These observations are consistent with the hypothesis that BRCA2, but not BRCA1, is a tumor suppressor gene related to prostate cancer risk.[117] The absence of mutation information on the 130 unstudied cases limits the value of this observation. A recent review of the relationship between germline mutations in BRCA2 and prostate cancer risk, supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families, but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[118]

Three Polish BRCA1 founder mutations (C16G, 4153delA, 5382insC) were studied in 1,793 Polish prostate cancer cases and 4,570 controls. Overall, the prevalence of the three mutations combined was identical in cases and controls. However, most common mutation, 5382insC, occurred in 0.06% of cases versus 0.37% of controls, suggesting that this specific variant is not likely to be associated with increased prostate cancer risk. Furthermore, the presence of either one of the other two mutations was associated with a 3.6-fold increase in prostate cancer risk (P = 0.045), and an even greater risk (OR = 12; P = 0.0004) of familial prostate cancer. These data suggest that prostate cancer risk in BRCA1 mutation carriers varies with the location of the mutation, i.e., there is a correlation between genotype and phenotype.[119] This observation might explain some of the inconsistencies encountered in prior studies of this association, since populations may have varied relative to the proportion of persons with specific pathogenic BRCA1 mutations.

Thus, the literature suggests that there may be a modest increase in prostate cancer risk among men with one of the Ashkenazi founder mutations, and a more substantial increase in risk among BRCA2 carriers in general; the risk is unclear among BRCA1 mutation carriers. These observations may comprise one of many factors that a man contemplating BRCA mutation testing might consider. Uncertainties regarding screening and management of men at increased risk of prostate cancer make it difficult to encourage BRCA mutation testing solely for prostate cancer risk management. (Refer to the Mutations in BRCA1 and BRCA2 section of the PDQ summary on Genetics of Breast and Ovarian Cancer and the Screening section of this summary for more information about testing for BRCA1 and BRCA2.)

The tumor suppressor gene Kruppel-like factor 6 (KLF6), located on chromosome 10p15, is a zinc finger transcription factor potentially associated with prostate cancer risk. Somatic mutations and allelic loss of KLF6 have been found in tumors of several primary neoplasms, including prostate cancer.[120] A germline mutation in KLF6 (IVS1-27G>A) appears to have a novel mechanism of gene inactivation: generation of alternatively spliced products that antagonize wild-type gene function.[121] However, data are inconsistent regarding the association of germline mutations in KLF6 and hereditary prostate cancer. A Finnish study of 69 prostate cancer families did not identify an association between KLF6 mutations and prostate cancer susceptibility.[122] The germline KLF6 SNP described above, IVS1-27G>A, was found to increase the RR of prostate cancer in a U.S. study of 3,411 men (RR = 1.61, P = .01; 95% CI, 1.20–2.16).[121] However, the prostate cancer risk associated with the IVS1-27G>A SNP was not detected in a study of 300 Jewish prostate cancer families.[123] In fact, the A allele, which was previously shown to be more common in U.S. men with prostate cancer and associated with the creation of splice variants, was significantly less common among cases than among controls in this Israeli study (49/804 alleles in cases compared with 55/600 control alleles; P = .030).

The alpha methylacyl-CoA racemase (AMACR) gene, located at 5p13.3, encodes a protein that is localized to peroxisomes and mitochondria and plays an important role in the metabolism of branch-chained fatty acids. The protein has been shown to be overexpressed in many cancers including prostate cancer. AMACR resequencing experiments using DNA from probands in HPC families were conducted.[124] From the 17 sequence variants identified, 11 SNPs were selected for genotyping in 159 HPC probands, 245 sporadic prostate cancer cases and 211 controls. Several variants (including M9V, G1157D, S291L, and K277E) were shown to be associated with HPC (but not sporadic prostate cancer). A haplotype-tagging strategy was used to test for association between genetic variation in AMACR and prostate cancer in a set of siblings discordant for prostate cancer who are participating in a research study focused on early-onset and/or HPC.[125] The strongest evidence for association was for SNP rs3195676 (M9V) with an OR of 0.58 (95% CI, 0.38 – 0.90, P = 0.01 for a recessive model). The reported magnitude and direction of the association observed for this SNP was similar between this study and previously mentioned AMACR resequencing experiments.[124] A nested case-control study was conducted using samples from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial to test for potential association between 7 AMACR SNPs and prostate cancer including M9V.[126] No association was detected between any of the SNPs and prostate cancer. Note that the prostate cancer cases in the PLCO study are all older than 55 years and not specifically enriched for family history. Risk for prostate cancer was reduced, however, in men who reported using ibuprofen who also had specific alleles and 4 SNPs (M9V, D175G, S201L and K77E) or a specific six-SNP haplotype. Ibuprofen mediates its anti-inflammatory effect through COX2 inhibition; AMACR contributes to the conversion of the COX-inactive to the COX-active form of ibuprofen. This observation suggests that these AMACR SNPs may alter enzyme function although experiments have not been conducted to directly test this hypothesis.

Individuals who were heterozygous for one of the Nijmegen Breakage syndrome (NBS) founder mutations identified in Poland may be at increased risk of prostate cancer.[127] NBS is a rare autosomal recessive cancer susceptibility disorder of childhood that is characterized by growth retardation, facial dysmorphism, immunodeficiency, and a predisposition to lymphoma and leukemia in patients with germline biallelic (e.g., homozygous) mutations. NBS1, located on chromosome 8q, has an important role in DNA repair and is part of the ataxia telangiectasia pathway. Recent observations have suggested that there may be an increased risk of cancer among heterozygous carriers of mutations in a number of genes involved in response to DNA damage, such as xeroderma pigmentosum [128] and ataxia telangiectasia.[129,130] Polish investigators analyzed the prevalence of an NBS1 founder mutation in a sample of 56 men with familial prostate cancer, 305 men with sporadic cancer, and control subjects who included men, women, and newborns. Cases with a positive family history were 16 times more likely to be mutation carriers than were controls (P <.0001). LOH was commonly observed in mutation-associated prostate cancers, with preferential loss of the wild-type allele.[127] A collaborative report from five groups participating in the ICPCG demonstrated a carrier frequency of 0.22% (2 of 909) for probands with familial prostate cancer and 0.25% (3 of 1,218) for men with sporadic cancer for the founder 657del5 mutation. Although this mutation was not detected in any of the 293 unaffected family members, the low frequency of the founder mutation suggests that NBS1 mutations do not contribute to a significant proportion of prostate cancer cases.[131]

In the first report of possible germline CHEK2 variants in men with prostate cancer, mutations were identified in 4.8% of 578 prostate cancer patients and in none of 423 unaffected men.[132] Nine of 149 multiplex prostate cancer families were also found to have germline CHEK2 mutations. The I157T substitution was detected in equal numbers of cases and controls and thus was felt to likely represent a polymorphism. Functional studies of additional identified variants revealed substantial reductions in CHEK2 protein levels and/or other functional changes that suggest CHEK2 mutations contribute to prostate carcinogenesis.[132,133] Subsequently, Polish investigators sequenced the CHEK2 gene in 140 patients with prostate cancer, and then analyzed the three detected variants in a larger series of prostate cancer cases and controls.[134] CHEK2 truncating mutations were identified in 9 of 1,921 controls (0.5%) and in 11 of 690 (1.6%) unselected patients with prostate cancer (OR = 3.4; P = .004). These same mutations were also found in 4 of 98 familial prostate cases (OR = 9.0; P = .0002). The I157T missense variant was also more frequent in men with prostate cancer (7.8%) than in controls (4.8%) (OR = 1.7; P = .03), and was identified in 16% of men with familial prostate cancer (OR = 3.8; P = .00002). LOH was not observed in any of the five men with truncating CHEK2 mutations. A follow-up to this study has been reported from Poland with 1,864 prostate cancer patients and 5,496 controls. All three founder mutations as well as a large germline deletion of exons 9 and 10 (5395-bp deletion) were genotyped. The truncating mutation 1100delC was identified in 14 of 1,864 (0.8%) unselected prostate cancer cases and 3 of 249 (1.2%) familial cases (OR = 3.5; P = .002 and OR = 5.6; P = .02, respectively). A significant association with another truncating mutation (IVS2+1G→A) was identified in 5 of 249 (2.0%) familial cases that had the mutation (OR = 5.1; P = .002). The missense mutation I157T was detected in 142 of 1,864 (7.6%) unselected prostate cancer cases and in 30 of 249 (12%) familial cases (OR = 1.6; P <.001 and OR = 2.7; P <.001, respectively). The large deletion in exons 9 and 10 accounted for 4 of 249 (1.6%) familial cases (OR = 3.7; P = .03). Overall, it appears that there are at least four founder mutations in the CHEK2 gene, which account for an estimated 7% of patients with prostate cancer in the Polish population. The most common missense mutation is I157T, and the most common truncating mutation is 5395-bp deletion. These reports suggest that truncating and missense mutations in CHEK2 may play a role in prostate cancer susceptibility.[135] However, a recent molecular analysis designed specifically to assess the role of seven different CHEK2 coding variants (including 1100delC) in Ashkenazi Jewish men with prostate cancer, suggested that germline mutations in this gene have a minor role, if any role at all, in modifying the risk of prostate cancer in Ashkenazi Jewish men. This conclusion is limited by the relatively small number of individuals in whom CHEK2 sequencing was performed.[136]

Table 3 summarizes the candidate genes for prostate cancer susceptibility, their chromosomal location, and availability of clinical testing.

To summarize, studies to date have mapped site-specific prostate cancer susceptibility loci to chromosomes 1q24–25 (HPC1), 1q42.2–43 (PCAP), 1p36 (CAPB), Xq27–2 (HPCX), 20q13 (HPC20), 17p (ELAC2/HPC2), and 8p. Other studies have suggested that prostate cancer may be part of the cancer spectrum of syndromes that include a more diverse set of malignancies, such as seems to be the case for BRCA2 and, perhaps, BRCA1. Both linkage and candidate gene studies have been complicated by the late-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for HPC, as suggested by both segregation and linkage studies. In this respect, HPC resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer).

Linkage studies may be used to evaluate the possibility that an HPC gene might exist in a particular family, but this analytic approach is currently being done only in the research setting. Until the specific genes and mutations involved are identified, it is difficult to establish the analytical validity of this approach. Without a validated laboratory test, clinical validity and clinical utility cannot be measured. At present, clinical germline mutation testing for HPC susceptibility is not available.

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The chromosomal regions with modest-to-strong statistical significance (LOD score of 2 or more) include the following chromosomes:

• 2q23 [31]
• 3p14 (ECOG-01Y97) [141]
• 3p24–26 [12,47,142]
• 4q21 [31]
• 4q25 [143]
• 5q11–12 [12,48]
• 5q35 [12,144]
• 6p22.3 [45]
• 7q [45]
• 8q13 [12]
• 9q34 [31]
• 11q22 [12]
• 13q14 [12]
• 15q11 [12]
• 16p13 [12]
• 16q23 [17]
• 17q21–22 [12,46,143,145,146]
• 19q [144]
• 19p13.3 [48]
• 22q12 [12,147]
• Xq12 [12]

Combined analyses have helped to prioritize candidate regions for further study.[12]

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study on 77 families with four or more affected men. Multipoint heterogeneity LOD (hLOD) scores greater than or equal to 1.3 and less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint hLOD score of 1.08) and 22q12 (multipoint hLOD score of 0.91).[12,148]

A study describes a linkage analysis targeting families with clinically aggressive prostate cancer (defined by Gleason grade ≥7, PSA ≥20 ng/mL, and cancer stage). One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (hLOD score of 2.18) and 22q12.3-q13.1 (hLOD score of 1.90).[13] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[147] No candidate genes have been identified. An analysis of high risk pedigrees from Utah provides an overview of this strategy.[149]

A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of HPC as well as one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a case revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[150] This observation awaits confirmation.

Genome-wide searches are showing great promise in identifying common, low-penetrance susceptibility alleles for many complex diseases,[151] including prostate cancer. In contrast to assessing candidate genes and/or alleles, genome-wide association studies (GWAS) involve comparing a very large set of genetic variants spread throughout the genome. This approach can be contrasted with linkage studies in which co-segregation of a genetic trait and genetic variants within multiplex families is assessed and with candidate gene studies which focus on one or more known genes that are biologically implicated in the disease. The current paradigm uses sets of 100,000 to 1,000,000 SNPs that are chosen to capture a large portion of common variation within the genome based on the HapMap project.[152,153] The SNPs that are studied in most GWAS are common, with minor allele frequencies, greater than 1% to 5%, in the specific population under study (e.g., men of European ancestry).

By comparing allele frequencies between a large number of cases and controls, typically 1,000 or more of each, and validating promising signals in replication sets of subjects, very robust statistical signals of association have been obtained.[154-156] The strong correlation between many SNPs that are physically close to each other on the chromosome (linkage disequilibrium) allows one to “scan” the genome for susceptibility alleles even if the biologically relevant variant is not within the tested set of SNPs. While this between–SNP correlation allows one to interrogate the majority of the genome without having to assay every SNP, when a validated association is obtained, it is not usually obvious which of the many correlated variants is the causal one. Another issue regarding GWAS is that studies that are focused on admixed groups need to be wary of the potential for population stratification which can lead to false-positive association signals when the frequency of genetic variants and the frequency of the disease under study are both increased in a population, such as prostate cancer in African American men. Finally, allelic heterogeneity (where multiple variants in the same gene can increase or decrease the risk for prostate cancer) can impact the results of GWAS. Additional detail can be found elsewhere.[157]

A two-stage GWAS was conducted for prostate cancer susceptibility.[158] In the first stage, 527,869 SNPs were studied using 1,172 cases and 1,157 controls of European ancestry from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening trial. Approximately 5% of the SNPs (26,598), those with the most evidence for disease association, were taken to the second stage and tested in a set of 3,941 cases and 3,964 controls of European origin derived from four additional study populations. Combined joint analysis using the initial scan results with those from the four follow up studies confirmed the association between prostate cancer and the hepatocyte nuclear factor-1-beta (HNF1B) gene, a finding that has been previously reported.[87,146] Several additional loci approximated or achieved the genome-wide level of statistical significance (p < 10^-7). These loci included rs10896449 in the promoter of MSMB (10q11.2), rs10896449 at 11q13, rs4962416 in the fifth intron of CTBP2 (chromosome 10) and rs10486567 in the second intron of JAZF1 (7p15).

A GWAS conducted in the United Kingdom and Australia compared 1,854 prostate cancer cases with 1,894 controls.[159] This study used cases that were diagnosed based on clinical symptoms, rather than PSA screening, and was enriched for genetic susceptibility through selection of men with early-onset prostate cancer (diagnosis before age 60 years) and/or family history. The DNA samples were typed using 569,243 SNPs, and 53 SNPs were found to be significantly associated with prostate cancer at the p < 10^-6 level. Twenty of the 53 SNPs were at 8q24 and six were at 17q12;[146] both regions have been implicated in prior studies of prostate cancer risk. Using an alternative design (family-based association) the 17q12 finding has been corroborated particularly in hereditary prostate cancer and early-onset prostate cancer.[160] Eleven SNPs from the previously described study [159] were subsequently studied in a second-stage sample comprising of 3,268 cases and 3,366 controls. Seven SNPs were independently associated with prostate cancer in this analysis including SNPs on chromosomes 3, 6, 7, 10, 11, 19 and X. Of note, the MSMB gene at 10q11.2 was implicated in both the PLCO and U.K. studies. A confirmatory study using data from the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) consortium, which included 7,370 cases and 5,742 controls, reported increasing ORs for six of the SNPs previously identified in the United Kingdom/Australia study. As the number of risk alleles increased the OR of prostate cancer increased (OR = 1.0 to OR = 3.5 for 0 vs. six risk alleles, respectively).[161]

To identify additional variants associated with prostate cancer, two candidate SNPs were selected from a prior GWAS[146] based on either being X-linked (rs5945572; Xp11.22) or associated with aggressive prostate cancer (Gleason ≥7 and/or ≥T3 and/or node positive and/or metastasis) (rs2710646 2p15).[162] Using the Utah CEPH HapMap data, several SNPs not represented in the prior study were selected for genotyping in 1,500 Icelandic cases and 800 Icelandic controls based on whether there was correlation with either of the candidate variants, rs5945572 or rs2710646. None of the newly selected SNPs were found to be more strongly associated with prostate cancer than the two candidate variants. The original two SNPs were then analyzed in seven additional prostate cancer case-control studies of individuals of European descent. In the combined case-control study group, the two SNPs revealed an OR = 1.24 (P = 2.57x10^-10) for rs5945572 and OR = 1.15 (P = 2.23x10^-6) for rs2710646. Combining the new data with the prior study strengthened these associations. The association between rs5945572 and prostate cancer risk was not related to early-onset or aggressive prostate cancer. However, the frequency of rs2710646 was higher in aggressive prostate cancer versus those with less aggressive disease, OR = 1.1 (P = 2.6x10^-3). In summary, both SNPs were associated with prostate cancer, with estimated population attributable risks in individuals of European descent of 7% for rs5945572 (Xp11.22) and 5% for rs2710646 (2p15).[162]

In an exploratory, but relatively underpowered GWAS targeting aggressive prostate cancer, a SNP within DAB21P (a proposed prostate tumor suppressor gene) was associated with prostate cancer risk (OR = 1.27, 95% CI, 1.10–1.48; P = .0017). This is a novel finding but the analysis did not achieve genome-wide levels of statistical significance; replication in further studies is awaited.[163]

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the biologically relevant variants and the mechanism(s) by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk and more risk variants are likely to be identified in the future. Until their individual and collective influences on cancer risk are evaluated prospectively, their clinical relevance is unclear.

References

1. Ostrander EA, Stanford JL: Genetics of prostate cancer: too many loci, too few genes. Am J Hum Genet 67 (6): 1367-75, 2000.  [PUBMED Abstract]
   
   
2. Conlon EM, Goode EL, Gibbs M, et al.: Oligogenic segregation analysis of hereditary prostate cancer pedigrees: evidence for multiple loci affecting age at onset. Int J Cancer 105 (5): 630-5, 2003.  [PUBMED Abstract]
   
   
3. Gong G, Oakley-Girvan I, Wu AH, et al.: Segregation analysis of prostate cancer in 1,719 white, African-American and Asian-American families in the United States and Canada. Cancer Causes Control 13 (5): 471-82, 2002.  [PUBMED Abstract]
   
   
4. Verhage BA, Baffoe-Bonnie AB, Baglietto L, et al.: Autosomal dominant inheritance of prostate cancer: a confirmatory study. Urology 57 (1): 97-101, 2001.  [PUBMED Abstract]
   
   
5. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998.  [PUBMED Abstract]
   
   
6. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992.  [PUBMED Abstract]
   
   
7. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997.  [PUBMED Abstract]
   
   
8. Cui J, Staples MP, Hopper JL, et al.: Segregation analyses of 1,476 population-based Australian families affected by prostate cancer. Am J Hum Genet 68 (5): 1207-18, 2001.  [PUBMED Abstract]
   
   
9. Easton DF, Schaid DJ, Whittemore AS, et al.: Where are the prostate cancer genes?--A summary of eight genome wide searches. Prostate 57 (4): 261-9, 2003.  [PUBMED Abstract]
   
   
10. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993.  [PUBMED Abstract]
    
    
11. Jemal A, Murray T, Samuels A, et al.: Cancer statistics, 2003. CA Cancer J Clin 53 (1): 5-26, 2003 Jan-Feb.  [PUBMED Abstract]
    
    
12. Xu J, Dimitrov L, Chang BL, et al.: A combined genomewide linkage scan of 1,233 families for prostate cancer-susceptibility genes conducted by the international consortium for prostate cancer genetics. Am J Hum Genet 77 (2): 219-29, 2005.  [PUBMED Abstract]
    
    
13. Stanford JL, McDonnell SK, Friedrichsen DM, et al.: Prostate cancer and genetic susceptibility: a genome scan incorporating disease aggressiveness. Prostate 66 (3): 317-25, 2006.  [PUBMED Abstract]
    
    
14. Chang BL, Isaacs SD, Wiley KE, et al.: Genome-wide screen for prostate cancer susceptibility genes in men with clinically significant disease. Prostate 64 (4): 356-61, 2005.  [PUBMED Abstract]
    
    
15. Lange EM, Ho LA, Beebe-Dimmer JL, et al.: Genome-wide linkage scan for prostate cancer susceptibility genes in men with aggressive disease: significant evidence for linkage at chromosome 15q12. Hum Genet 119 (4): 400-7, 2006.  [PUBMED Abstract]
    
    
16. Witte JS, Goddard KA, Conti DV, et al.: Genomewide scan for prostate cancer-aggressiveness loci. Am J Hum Genet 67 (1): 92-9, 2000.  [PUBMED Abstract]
    
    
17. Witte JS, Suarez BK, Thiel B, et al.: Genome-wide scan of brothers: replication and fine mapping of prostate cancer susceptibility and aggressiveness loci. Prostate 57 (4): 298-308, 2003.  [PUBMED Abstract]
    
    
18. Slager SL, Zarfas KE, Brown WM, et al.: Genome-wide linkage scan for prostate cancer aggressiveness loci using families from the University of Michigan Prostate Cancer Genetics Project. Prostate 66 (2): 173-9, 2006.  [PUBMED Abstract]
    
    
19. Slager SL, Schaid DJ, Cunningham JM, et al.: Confirmation of linkage of prostate cancer aggressiveness with chromosome 19q. Am J Hum Genet 72 (3): 759-62, 2003.  [PUBMED Abstract]
    
    
20. Smith JR, Freije D, Carpten JD, et al.: Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science 274 (5291): 1371-4, 1996.  [PUBMED Abstract]
    
    
21. Grönberg H, Xu J, Smith JR, et al.: Early age at diagnosis in families providing evidence of linkage to the hereditary prostate cancer locus (HPC1) on chromosome 1. Cancer Res 57 (21): 4707-9, 1997.  [PUBMED Abstract]
    
    
22. Grönberg H, Isaacs SD, Smith JR, et al.: Characteristics of prostate cancer in families potentially linked to the hereditary prostate cancer 1 (HPC1) locus. JAMA 278 (15): 1251-5, 1997.  [PUBMED Abstract]
    
    
23. McIndoe RA, Stanford JL, Gibbs M, et al.: Linkage analysis of 49 high-risk families does not support a common familial prostate cancer-susceptibility gene at 1q24-25. Am J Hum Genet 61 (2): 347-53, 1997.  [PUBMED Abstract]
    
    
24. Berthon P, Valeri A, Cohen-Akenine A, et al.: Predisposing gene for early-onset prostate cancer, localized on chromosome 1q42.2-43. Am J Hum Genet 62 (6): 1416-24, 1998.  [PUBMED Abstract]
    
    
25. Eeles RA, Durocher F, Edwards S, et al.: Linkage analysis of chromosome 1q markers in 136 prostate cancer families. The Cancer Research Campaign/British Prostate Group U.K. Familial Prostate Cancer Study Collaborators. Am J Hum Genet 62 (3): 653-8, 1998.  [PUBMED Abstract]
    
    
26. Goode EL, Stanford JL, Chakrabarti L, et al.: Linkage analysis of 150 high-risk prostate cancer families at 1q24-25. Genet Epidemiol 18 (3): 251-75, 2000.  [PUBMED Abstract]
    
    
27. Cooney KA, McCarthy JD, Lange E, et al.: Prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. J Natl Cancer Inst 89 (13): 955-9, 1997.  [PUBMED Abstract]
    
    
28. Hsieh CL, Oakley-Girvan I, Gallagher RP, et al.: Re: prostate cancer susceptibility locus on chromosome 1q: a confirmatory study. J Natl Cancer Inst 89 (24): 1893-4, 1997.  [PUBMED Abstract]
    
    
29. Neuhausen SL, Farnham JM, Kort E, et al.: Prostate cancer susceptibility locus HPC1 in Utah high-risk pedigrees. Hum Mol Genet 8 (13): 2437-42, 1999.  [PUBMED Abstract]
    
    
30. Xu J: Combined analysis of hereditary prostate cancer linkage to 1q24-25: results from 772 hereditary prostate cancer families from the International Consortium for Prostate Cancer Genetics. Am J Hum Genet 66 (3): 945-57, 2000.  [PUBMED Abstract]
    
    
31. Xu J, Gillanders EM, Isaacs SD, et al.: Genome-wide scan for prostate cancer susceptibility genes in the Johns Hopkins hereditary prostate cancer families. Prostate 57 (4): 320-5, 2003.  [PUBMED Abstract]
    
    
32. Brown WM, Lange EM, Chen H, et al.: Hereditary prostate cancer in African American families: linkage analysis using markers that map to five candidate susceptibility loci. Br J Cancer 90 (2): 510-4, 2004.  [PUBMED Abstract]
    
    
33. Wang L, McDonnell SK, Elkins DA, et al.: Analysis of the RNASEL gene in familial and sporadic prostate cancer. Am J Hum Genet 71 (1): 116-23, 2002.  [PUBMED Abstract]
    
    
34. Chen H, Griffin AR, Wu YQ, et al.: RNASEL mutations in hereditary prostate cancer. J Med Genet 40 (3): e21, 2003.  [PUBMED Abstract]
    
    
35. Rökman A, Ikonen T, Seppälä EH, et al.: Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer. Am J Hum Genet 70 (5): 1299-304, 2002.  [PUBMED Abstract]
    
    
36. Rennert H, Bercovich D, Hubert A, et al.: A novel founder mutation in the RNASEL gene, 471delAAAG, is associated with prostate cancer in Ashkenazi Jews. Am J Hum Genet 71 (4): 981-4, 2002.  [PUBMED Abstract]
    
    
37. Casey G, Neville PJ, Plummer SJ, et al.: RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases. Nat Genet 32 (4): 581-3, 2002.  [PUBMED Abstract]
    
    
38. Wiklund F, Jonsson BA, Brookes AJ, et al.: Genetic analysis of the RNASEL gene in hereditary, familial, and sporadic prostate cancer. Clin Cancer Res 10 (21): 7150-6, 2004.  [PUBMED Abstract]
    
    
39. Li H, Tai BC: RNASEL gene polymorphisms and the risk of prostate cancer: a meta-analysis. Clin Cancer Res 12 (19): 5713-9, 2006.  [PUBMED Abstract]
    
    
40. Cancel-Tassin G, Latil A, Valéri A, et al.: PCAP is the major known prostate cancer predisposing locus in families from south and west Europe. Eur J Hum Genet 9 (2): 135-42, 2001.  [PUBMED Abstract]
    
    
41. Whittemore AS, Lin IG, Oakley-Girvan I, et al.: No evidence of linkage for chromosome 1q42.2-43 in prostate cancer. Am J Hum Genet 65 (1): 254-6, 1999.  [PUBMED Abstract]
    
    
42. Berry R, Schaid DJ, Smith JR, et al.: Linkage analyses at the chromosome 1 loci 1q24-25 (HPC1), 1q42.2-43 (PCAP), and 1p36 (CAPB) in families with hereditary prostate cancer. Am J Hum Genet 66 (2): 539-46, 2000.  [PUBMED Abstract]
    
    
43. Edwards S, Meitz J, Eles R, et al.: Results of a genome-wide linkage analysis in prostate cancer families ascertained through the ACTANE consortium. Prostate 57 (4): 270-9, 2003.  [PUBMED Abstract]
    
    
44. Cunningham JM, McDonnell SK, Marks A, et al.: Genome linkage screen for prostate cancer susceptibility loci: results from the Mayo Clinic Familial Prostate Cancer Study. Prostate 57 (4): 335-46, 2003.  [PUBMED Abstract]
    
    
45. Janer M, Friedrichsen DM, Stanford JL, et al.: Genomic scan of 254 hereditary prostate cancer families. Prostate 57 (4): 309-19, 2003.  [PUBMED Abstract]
    
    
46. Lange EM, Gillanders EM, Davis CC, et al.: Genome-wide scan for prostate cancer susceptibility genes using families from the University of Michigan prostate cancer genetics project finds evidence for linkage on chromosome 17 near BRCA1. Prostate 57 (4): 326-34, 2003.  [PUBMED Abstract]
    
    
47. Schleutker J, Baffoe-Bonnie AB, Gillanders E, et al.: Genome-wide scan for linkage in Finnish hereditary prostate cancer (HPC) families identifies novel susceptibility loci at 11q14 and 3p25-26. Prostate 57 (4): 280-9, 2003.  [PUBMED Abstract]
    
    
48. Wiklund F, Gillanders EM, Albertus JA, et al.: Genome-wide scan of Swedish families with hereditary prostate cancer: suggestive evidence of linkage at 5q11.2 and 19p13.3. Prostate 57 (4): 290-7, 2003.  [PUBMED Abstract]
    
    
49. Xu J, Meyers D, Freije D, et al.: Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 20 (2): 175-9, 1998.  [PUBMED Abstract]
    
    
50. Lesko SM, Rosenberg L, Shapiro S: Family history and prostate cancer risk. Am J Epidemiol 144 (11): 1041-7, 1996.  [PUBMED Abstract]
    
    
51. Lange EM, Chen H, Brierley K, et al.: Linkage analysis of 153 prostate cancer families over a 30-cM region containing the putative susceptibility locus HPCX. Clin Cancer Res 5 (12): 4013-20, 1999.  [PUBMED Abstract]
    
    
52. Peters MA, Jarvik GP, Janer M, et al.: Genetic linkage analysis of prostate cancer families to Xq27-28. Hum Hered 51 (1-2): 107-13, 2001.  [PUBMED Abstract]
    
    
53. Farnham JM, Camp NJ, Swensen J, et al.: Confirmation of the HPCX prostate cancer predisposition locus in large Utah prostate cancer pedigrees. Hum Genet 116 (3): 179-85, 2005.  [PUBMED Abstract]
    
    
54. Baffoe-Bonnie AB, Smith JR, Stephan DA, et al.: A major locus for hereditary prostate cancer in Finland: localization by linkage disequilibrium of a haplotype in the HPCX region. Hum Genet 117 (4): 307-16, 2005.  [PUBMED Abstract]
    
    
55. Yaspan BL, McReynolds KM, Elmore JB, et al.: A haplotype at chromosome Xq27.2 confers susceptibility to prostate cancer. Hum Genet 123 (4): 379-86, 2008.  [PUBMED Abstract]
    
    
56. Gibbs M, Stanford JL, McIndoe RA, et al.: Evidence for a rare prostate cancer-susceptibility locus at chromosome 1p36. Am J Hum Genet 64 (3): 776-87, 1999.  [PUBMED Abstract]
    
    
57. Badzioch M, Eeles R, Leblanc G, et al.: Suggestive evidence for a site specific prostate cancer gene on chromosome 1p36. The CRC/BPG UK Familial Prostate Cancer Study Coordinators and Collaborators. The EU Biomed Collaborators. J Med Genet 37 (12): 947-9, 2000.  [PUBMED Abstract]
    
    
58. Tavtigian SV, Simard J, Teng DH, et al.: A candidate prostate cancer susceptibility gene at chromosome 17p. Nat Genet 27 (2): 172-80, 2001.  [PUBMED Abstract]
    
    
59. Xu J, Zheng SL, Carpten JD, et al.: Evaluation of linkage and association of HPC2/ELAC2 in patients with familial or sporadic prostate cancer. Am J Hum Genet 68 (4): 901-11, 2001.  [PUBMED Abstract]
    
    
60. Wang L, McDonnell SK, Elkins DA, et al.: Role of HPC2/ELAC2 in hereditary prostate cancer. Cancer Res 61 (17): 6494-9, 2001.  [PUBMED Abstract]
    
    
61. Rebbeck TR, Walker AH, Zeigler-Johnson C, et al.: Association of HPC2/ELAC2 genotypes and prostate cancer. Am J Hum Genet 67 (4): 1014-9, 2000.  [PUBMED Abstract]
    
    
62. Camp NJ, Tavtigian SV: Meta-analysis of associations of the Ser217Leu and Ala541Thr variants in ELAC2 (HPC2) and prostate cancer. Am J Hum Genet 71 (6): 1475-8, 2002.  [PUBMED Abstract]
    
    
63. Severi G, Giles GG, Southey MC, et al.: ELAC2/HPC2 polymorphisms, prostate-specific antigen levels, and prostate cancer. J Natl Cancer Inst 95 (11): 818-24, 2003.  [PUBMED Abstract]
    
    
64. Berry R, Schroeder JJ, French AJ, et al.: Evidence for a prostate cancer-susceptibility locus on chromosome 20. Am J Hum Genet 67 (1): 82-91, 2000.  [PUBMED Abstract]
    
    
65. Bock CH, Cunningham JM, McDonnell SK, et al.: Analysis of the prostate cancer-susceptibility locus HPC20 in 172 families affected by prostate cancer. Am J Hum Genet 68 (3): 795-801, 2001.  [PUBMED Abstract]
    
    
66. Zheng SL, Xu J, Isaacs SD, et al.: Evidence for a prostate cancer linkage to chromosome 20 in 159 hereditary prostate cancer families. Hum Genet 108 (5): 430-5, 2001.  [PUBMED Abstract]
    
    
67. Schaid DJ, Chang BL; International Consortium For Prostate Cancer Genetics.: Description of the International Consortium For Prostate Cancer Genetics, and failure to replicate linkage of hereditary prostate cancer to 20q13. Prostate 63 (3): 276-90, 2005.  [PUBMED Abstract]
    
    
68. Xu J, Zheng SL, Hawkins GA, et al.: Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23. Am J Hum Genet 69 (2): 341-50, 2001.  [PUBMED Abstract]
    
    
69. Xu J, Zheng SL, Komiya A, et al.: Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Nat Genet 32 (2): 321-5, 2002.  [PUBMED Abstract]
    
    
70. Xu J, Zheng SL, Komiya A, et al.: Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk. Am J Hum Genet 72 (1): 208-12, 2003.  [PUBMED Abstract]
    
    
71. Seppälä EH, Ikonen T, Autio V, et al.: Germ-line alterations in MSR1 gene and prostate cancer risk. Clin Cancer Res 9 (14): 5252-6, 2003.  [PUBMED Abstract]
    
    
72. Wang L, McDonnell SK, Cunningham JM, et al.: No association of germline alteration of MSR1 with prostate cancer risk. Nat Genet 35 (2): 128-9, 2003.  [PUBMED Abstract]
    
    
73. Miller DC, Zheng SL, Dunn RL, et al.: Germ-line mutations of the macrophage scavenger receptor 1 gene: association with prostate cancer risk in African-American men. Cancer Res 63 (13): 3486-9, 2003.  [PUBMED Abstract]
    
    
74. Sun J, Hsu FC, Turner AR, et al.: Meta-analysis of association of rare mutations and common sequence variants in the MSR1 gene and prostate cancer risk. Prostate 66 (7): 728-37, 2006.  [PUBMED Abstract]
    
    
75. Hawkins GA, Mychaleckyj JC, Zheng SL, et al.: Germline sequence variants of the LZTS1 gene are associated with prostate cancer risk. Cancer Genet Cytogenet 137 (1): 1-7, 2002.  [PUBMED Abstract]
    
    
76. Chang BL, Liu W, Sun J, et al.: Integration of somatic deletion analysis of prostate cancers and germline linkage analysis of prostate cancer families reveals two small consensus regions for prostate cancer genes at 8p. Cancer Res 67 (9): 4098-103, 2007.  [PUBMED Abstract]
    
    
77. Amundadottir LT, Sulem P, Gudmundsson J, et al.: A common variant associated with prostate cancer in European and African populations. Nat Genet 38 (6): 652-8, 2006.  [PUBMED Abstract]
    
    
78. Freedman ML, Haiman CA, Patterson N, et al.: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A 103 (38): 14068-73, 2006.  [PUBMED Abstract]
    
    
79. Schumacher FR, Feigelson HS, Cox DG, et al.: A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res 67 (7): 2951-6, 2007.  [PUBMED Abstract]
    
    
80. Suuriniemi M, Agalliu I, Schaid DJ, et al.: Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev 16 (4): 809-14, 2007.  [PUBMED Abstract]
    
    
81. Wang L, McDonnell SK, Slusser JP, et al.: Two common chromosome 8q24 variants are associated with increased risk for prostate cancer. Cancer Res 67 (7): 2944-50, 2007.  [PUBMED Abstract]
    
    
82. Yeager M, Orr N, Hayes RB, et al.: Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39 (5): 645-9, 2007.  [PUBMED Abstract]
    
    
83. Zheng SL, Sun J, Cheng Y, et al.: Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst 99 (20): 1525-33, 2007.  [PUBMED Abstract]
    
    
84. Savage SA, Greene MH: The evidence for prostate cancer risk loci at 8q24 grows stronger. J Natl Cancer Inst 99 (20): 1499-501, 2007.  [PUBMED Abstract]
    
    
85. Salinas CA, Kwon E, Carlson CS, et al.: Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk. Cancer Epidemiol Biomarkers Prev 17 (5): 1203-13, 2008.  [PUBMED Abstract]
    
    
86. Gudmundsson J, Sulem P, Manolescu A, et al.: Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39 (5): 631-7, 2007.  [PUBMED Abstract]
    
    
87. Haiman CA, Patterson N, Freedman ML, et al.: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 39 (5): 638-44, 2007.  [PUBMED Abstract]
    
    
88. Robbins C, Torres JB, Hooker S, et al.: Confirmation study of prostate cancer risk variants at 8q24 in African Americans identifies a novel risk locus. Genome Res 17 (12): 1717-22, 2007.  [PUBMED Abstract]
    
    
89. Cheng I, Plummer SJ, Jorgenson E, et al.: 8q24 and prostate cancer: association with advanced disease and meta-analysis. Eur J Hum Genet 16 (4): 496-505, 2008.  [PUBMED Abstract]
    
    
90. Sun J, Lange EM, Isaacs SD, et al.: Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients. Prostate 68 (5): 489-97, 2008.  [PUBMED Abstract]
    
    
91. Beebe-Dimmer JL, Levin AM, Ray AM, et al.: Chromosome 8q24 markers: risk of early-onset and familial prostate cancer. Int J Cancer 122 (12): 2876-9, 2008.  [PUBMED Abstract]
    
    
92. Thompson D, Easton DF; Breast Cancer Linkage Consortium.: Cancer Incidence in BRCA1 mutation carriers. J Natl Cancer Inst 94 (18): 1358-65, 2002.  [PUBMED Abstract]
    
    
93. Liede A, Karlan BY, Narod SA: Cancer risks for male carriers of germline mutations in BRCA1 or BRCA2: a review of the literature. J Clin Oncol 22 (4): 735-42, 2004.  [PUBMED Abstract]
    
    
94. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91 (15): 1310-6, 1999.  [PUBMED Abstract]
    
    
95. Thompson D, Easton D; Breast Cancer Linkage Consortium.: Variation in cancer risks, by mutation position, in BRCA2 mutation carriers. Am J Hum Genet 68 (2): 410-9, 2001.  [PUBMED Abstract]
    
    
96. Nastiuk KL, Mansukhani M, Terry MB, et al.: Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men. Prostate 40 (3): 172-7, 1999.  [PUBMED Abstract]
    
    
97. Vazina A, Baniel J, Yaacobi Y, et al.: The rate of the founder Jewish mutations in BRCA1 and BRCA2 in prostate cancer patients in Israel. Br J Cancer 83 (4): 463-6, 2000.  [PUBMED Abstract]
    
    
98. Lehrer S, Fodor F, Stock RG, et al.: Absence of 185delAG mutation of the BRCA1 gene and 6174delT mutation of the BRCA2 gene in Ashkenazi Jewish men with prostate cancer. Br J Cancer 78 (6): 771-3, 1998.  [PUBMED Abstract]
    
    
99. Struewing JP, Abeliovich D, Peretz T, et al.: The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat Genet 11 (2): 198-200, 1995.  [PUBMED Abstract]
    
    
100. Oddoux C, Struewing JP, Clayton CM, et al.: The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%. Nat Genet 14 (2): 188-90, 1996.  [PUBMED Abstract]
     
     
101. Roa BB, Boyd AA, Volcik K, et al.: Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 14 (2): 185-7, 1996.  [PUBMED Abstract]
     
     
102. Struewing JP, Hartge P, Wacholder S, et al.: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336 (20): 1401-8, 1997.  [PUBMED Abstract]
     
     
103. Giusti RM, Rutter JL, Duray PH, et al.: A twofold increase in BRCA mutation related prostate cancer among Ashkenazi Israelis is not associated with distinctive histopathology. J Med Genet 40 (10): 787-92, 2003.  [PUBMED Abstract]
     
     
104. Kirchhoff T, Kauff ND, Mitra N, et al.: BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 10 (9): 2918-21, 2004.  [PUBMED Abstract]
     
     
105. Edwards SM, Kote-Jarai Z, Meitz J, et al.: Two percent of men with early-onset prostate cancer harbor germline mutations in the BRCA2 gene. Am J Hum Genet 72 (1): 1-12, 2003.  [PUBMED Abstract]
     
     
106. Agalliu I, Karlins E, Kwon EM, et al.: Rare germline mutations in the BRCA2 gene are associated with early-onset prostate cancer. Br J Cancer 97 (6): 826-31, 2007.  [PUBMED Abstract]
     
     
107. Thorlacius S, Olafsdottir G, Tryggvadottir L, et al.: A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13 (1): 117-9, 1996.  [PUBMED Abstract]
     
     
108. Thorlacius S, Sigurdsson S, Bjarnadottir H, et al.: Study of a single BRCA2 mutation with high carrier frequency in a small population. Am J Hum Genet 60 (5): 1079-84, 1997.  [PUBMED Abstract]
     
     
109. Johannesdottir G, Gudmundsson J, Bergthorsson JT, et al.: High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res 56 (16): 3663-5, 1996.  [PUBMED Abstract]
     
     
110. Sigurdsson S, Thorlacius S, Tomasson J, et al.: BRCA2 mutation in Icelandic prostate cancer patients. J Mol Med 75 (10): 758-61, 1997.  [PUBMED Abstract]
     
     
111. Hubert A, Peretz T, Manor O, et al.: The Jewish Ashkenazi founder mutations in the BRCA1/BRCA2 genes are not found at an increased frequency in Ashkenazi patients with prostate cancer. Am J Hum Genet 65 (3): 921-4, 1999.  [PUBMED Abstract]
     
     
112. Grönberg H, Ahman AK, Emanuelsson M, et al.: BRCA2 mutation in a family with hereditary prostate cancer. Genes Chromosomes Cancer 30 (3): 299-301, 2001.  [PUBMED Abstract]
     
     
113. Tryggvadóttir L, Vidarsdóttir L, Thorgeirsson T, et al.: Prostate cancer progression and survival in BRCA2 mutation carriers. J Natl Cancer Inst 99 (12): 929-35, 2007.  [PUBMED Abstract]
     
     
114. Agalliu I, Kwon EM, Zadory D, et al.: Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer. Clin Cancer Res 13 (3): 839-43, 2007.  [PUBMED Abstract]
     
     
115. Zuhlke KA, Madeoy JJ, Beebe-Dimmer J, et al.: Truncating BRCA1 mutations are uncommon in a cohort of hereditary prostate cancer families with evidence of linkage to 17q markers. Clin Cancer Res 10 (18 Pt 1): 5975-80, 2004.  [PUBMED Abstract]
     
     
116. Douglas JA, Levin AM, Zuhlke KA, et al.: Common variation in the BRCA1 gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (7): 1510-6, 2007.  [PUBMED Abstract]
     
     
117. Willems AJ, Dawson SJ, Samaratunga H, et al.: Loss of heterozygosity at the BRCA2 locus detected by multiplex ligation-dependent probe amplification is common in prostate cancers from men with a germline BRCA2 mutation. Clin Cancer Res 14 (10): 2953-61, 2008.  [PUBMED Abstract]
     
     
118. Ostrander EA, Udler MS: The role of the BRCA2 gene in susceptibility to prostate cancer revisited. Cancer Epidemiol Biomarkers Prev 17 (8): 1843-8, 2008.  [PUBMED Abstract]
     
     
119. Cybulski C, Górski B, Gronwald J, et al.: BRCA1 mutations and prostate cancer in Poland. Eur J Cancer Prev 17 (1): 62-6, 2008.  [PUBMED Abstract]
     
     
120. Narla G, Heath KE, Reeves HL, et al.: KLF6, a candidate tumor suppressor gene mutated in prostate cancer. Science 294 (5551): 2563-6, 2001.  [PUBMED Abstract]
     
     
121. Narla G, Difeo A, Reeves HL, et al.: A germline DNA polymorphism enhances alternative splicing of the KLF6 tumor suppressor gene and is associated with increased prostate cancer risk. Cancer Res 65 (4): 1213-22, 2005.  [PUBMED Abstract]
     
     
122. Koivisto PA, Hyytinen ER, Matikainen M, et al.: Kruppel-like factor 6 germ-line mutations are infrequent in Finnish hereditary prostate cancer. J Urol 172 (2): 506-7, 2004.  [PUBMED Abstract]
     
     
123. Bar-Shira A, Matarasso N, Rosner S, et al.: Mutation screening and association study of the candidate prostate cancer susceptibility genes MSR1, PTEN, and KLF6. Prostate 66 (10): 1052-60, 2006.  [PUBMED Abstract]
     
     
124. Zheng SL, Chang BL, Faith DA, et al.: Sequence variants of alpha-methylacyl-CoA racemase are associated with prostate cancer risk. Cancer Res 62 (22): 6485-8, 2002.  [PUBMED Abstract]
     
     
125. Levin AM, Zuhlke KA, Ray AM, et al.: Sequence variation in alpha-methylacyl-CoA racemase and risk of early-onset and familial prostate cancer. Prostate 67 (14): 1507-13, 2007.  [PUBMED Abstract]
     
     
126. Daugherty SE, Shugart YY, Platz EA, et al.: Polymorphic variants in alpha-methylacyl-CoA racemase and prostate cancer. Prostate 67 (14): 1487-97, 2007.  [PUBMED Abstract]
     
     
127. Cybulski C, Górski B, Debniak T, et al.: NBS1 is a prostate cancer susceptibility gene. Cancer Res 64 (4): 1215-9, 2004.  [PUBMED Abstract]
     
     
128. Swift M, Chase C: Cancer in families with xeroderma pigmentosum. J Natl Cancer Inst 62 (6): 1415-21, 1979.  [PUBMED Abstract]
     
     
129. Geoffroy-Perez B, Janin N, Ossian K, et al.: Variation in breast cancer risk of heterozygotes for ataxia-telangiectasia according to environmental factors. Int J Cancer 99 (4): 619-23, 2002.  [PUBMED Abstract]
     
     
130. Tamimi RM, Hankinson SE, Spiegelman D, et al.: Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case-control study. Breast Cancer Res 6 (4): R416-22, 2004.  [PUBMED Abstract]
     
     
131. Hebbring SJ, Fredriksson H, White KA, et al.: Role of the Nijmegen breakage syndrome 1 gene in familial and sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 15 (5): 935-8, 2006.  [PUBMED Abstract]
     
     
132. Dong X, Wang L, Taniguchi K, et al.: Mutations in CHEK2 associated with prostate cancer risk. Am J Hum Genet 72 (2): 270-80, 2003.  [PUBMED Abstract]
     
     
133. Wu X, Dong X, Liu W, et al.: Characterization of CHEK2 mutations in prostate cancer. Hum Mutat 27 (8): 742-7, 2006.  [PUBMED Abstract]
     
     
134. Cybulski C, Huzarski T, Górski B, et al.: A novel founder CHEK2 mutation is associated with increased prostate cancer risk. Cancer Res 64 (8): 2677-9, 2004.  [PUBMED Abstract]
     
     
135. Cybulski C, Wokołorczyk D, Huzarski T, et al.: A large germline deletion in the Chek2 kinase gene is associated with an increased risk of prostate cancer. J Med Genet 43 (11): 863-6, 2006.  [PUBMED Abstract]
     
     
136. Tischkowitz MD, Yilmaz A, Chen LQ, et al.: Identification and characterization of novel SNPs in CHEK2 in Ashkenazi Jewish men with prostate cancer. Cancer Lett 270 (1): 173-80, 2008.  [PUBMED Abstract]
     
     
137. Brose MS, Rebbeck TR, Calzone KA, et al.: Cancer risk estimates for BRCA1 mutation carriers identified in a risk evaluation program. J Natl Cancer Inst 94 (18): 1365-72, 2002.  [PUBMED Abstract]
     
     
138. Ford D, Easton DF, Stratton M, et al.: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62 (3): 676-89, 1998.  [PUBMED Abstract]
     
     
139. Rennert H, Zeigler-Johnson CM, Addya K, et al.: Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men. Cancer Epidemiol Biomarkers Prev 14 (4): 949-57, 2005.  [PUBMED Abstract]
     
     
140. Narla G, DiFeo A, Yao S, et al.: Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread. Cancer Res 65 (13): 5761-8, 2005.  [PUBMED Abstract]
     
     
141. Larson GP, Ding Y, Cheng LS, et al.: Genetic linkage of prostate cancer risk to the chromosome 3 region bearing FHIT. Cancer Res 65 (3): 805-14, 2005.  [PUBMED Abstract]
     
     
142. Rökman A, Baffoe-Bonnie AB, Gillanders E, et al.: Hereditary prostate cancer in Finland: fine-mapping validates 3p26 as a major predisposition locus. Hum Genet 116 (1-2): 43-50, 2005.  [PUBMED Abstract]
     
     
143. Gillanders EM, Xu J, Chang BL, et al.: Combined genome-wide scan for prostate cancer susceptibility genes. J Natl Cancer Inst 96 (16): 1240-7, 2004.  [PUBMED Abstract]
     
     
144. Schaid DJ, Stanford JL, McDonnell SK, et al.: Genome-wide linkage scan of prostate cancer Gleason score and confirmation of chromosome 19q. Hum Genet 121 (6): 729-35, 2007.  [PUBMED Abstract]
     
     
145. Zheng SL, Sun J, Wiklund F, et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 (9): 910-9, 2008.  [PUBMED Abstract]
     
     
146. Gudmundsson J, Sulem P, Steinthorsdottir V, et al.: Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet 39 (8): 977-83, 2007.  [PUBMED Abstract]
     
     
147. Camp NJ, Farnham JM, Cannon-Albright LA: Localization of a prostate cancer predisposition gene to an 880-kb region on chromosome 22q12.3 in Utah high-risk pedigrees. Cancer Res 66 (20): 10205-12, 2006.  [PUBMED Abstract]
     
     
148. Baffoe-Bonnie AB, Kittles RA, Gillanders E, et al.: Genome-wide linkage of 77 families from the African American Hereditary Prostate Cancer study (AAHPC). Prostate 67 (1): 22-31, 2007.  [PUBMED Abstract]
     
     
149. Christensen GB, Camp NJ, Farnham JM, et al.: Genome-wide linkage analysis for aggressive prostate cancer in Utah high-risk pedigrees. Prostate 67 (6): 605-13, 2007.  [PUBMED Abstract]
     
     
150. Johanneson B, Deutsch K, McIntosh L, et al.: Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer. Prostate 67 (7): 732-42, 2007.  [PUBMED Abstract]
     
     
151. Wellcome Trust Case Control Consortium.: Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447 (7145): 661-78, 2007.  [PUBMED Abstract]
     
     
152. The International HapMap Consortium.: The International HapMap Project. Nature 426 (6968): 789-96, 2003.  [PUBMED Abstract]
     
     
153. Thorisson GA, Smith AV, Krishnan L, et al.: The International HapMap Project Web site. Genome Res 15 (11): 1592-3, 2005.  [PUBMED Abstract]
     
     
154. Evans DM, Cardon LR: Genome-wide association: a promising start to a long race. Trends Genet 22 (7): 350-4, 2006.  [PUBMED Abstract]
     
     
155. Cardon LR: Genetics. Delivering new disease genes. Science 314 (5804): 1403-5, 2006.  [PUBMED Abstract]
     
     
156. Chanock SJ, Manolio T, Boehnke M, et al.: Replicating genotype-phenotype associations. Nature 447 (7145): 655-60, 2007.  [PUBMED Abstract]
     
     
157. Jorgenson E, Witte JS: Genome-wide association studies of cancer. Future Oncol 3 (4): 419-27, 2007.  [PUBMED Abstract]
     
     
158. Thomas G, Jacobs KB, Yeager M, et al.: Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40 (3): 310-5, 2008.  [PUBMED Abstract]
     
     
159. Eeles RA, Kote-Jarai Z, Giles GG, et al.: Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40 (3): 316-21, 2008.  [PUBMED Abstract]
     
     
160. Levin AM, Machiela MJ, Zuhlke KA, et al.: Chromosome 17q12 variants contribute to risk of early-onset prostate cancer. Cancer Res 68 (16): 6492-5, 2008.  [PUBMED Abstract]
     
     
161. Song H, Koessler T, Ahmed S, et al.: Association study of prostate cancer susceptibility variants with risks of invasive ovarian, breast, and colorectal cancer. Cancer Res 68 (21): 8837-42, 2008.  [PUBMED Abstract]
     
     
162. Gudmundsson J, Sulem P, Rafnar T, et al.: Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer. Nat Genet 40 (3): 281-3, 2008.  [PUBMED Abstract]
     
     
163. Duggan D, Zheng SL, Knowlton M, et al.: Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J Natl Cancer Inst 99 (24): 1836-44, 2007.  [PUBMED Abstract]
     
     

Back to Top

< Previous Section  |  Next Section >