Methods of Prostate Cancer Genetic Research
Introduction to linkage analyses
Candidate genes and susceptibility loci identified in linkage analyses
BRCA1 and BRCA2
Mismatch repair genes
Other potential prostate cancer genes
Other Regions Identified by Admixture Studies
Genome-wide Association Studies (GWAS)
Introduction to GWAS
Candidate genes and susceptibility loci identified in GWAS
Clinical application of GWAS findings
GWAS and insight into the mechanism of prostate cancer risk
GWAS in non-European populations
Genetic Modifiers of Prostate Cancer Aggressiveness
Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, highly penetrant in families, and have large effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.Linkage Analyses
Introduction to linkage analyses
The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.
Linkage studies are typically performed on high-risk kindreds in whom 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. Linkage analysis is affected by the following:
- 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 (e.g., utilization of screening).
- Gender differences in disease risk (not relevant in prostate cancer but remains relevant in linkage analysis for other conditions).
- Heterogeneity of disease in cases (e.g., aggressive vs. non-aggressive phenotype).
- The accuracy of family history information.
Furthermore, because a standard definition of hereditary prostate cancer (HPC) has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment. One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of HPC families. Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have HPC:
- Three or more affected first-degree relatives (father, brother, son).
- Affected relatives in three successive generations of either maternal or paternal lineages.
- At least two relatives affected at age 55 years or younger.
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 one in six, it is possible that families under study have men with both inherited and sporadic prostate cancer. 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 limited 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 PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.
One way to address inconsistencies between linkage studies is to require inclusion criteria that defines clinically significant disease (e.g., Gleason score ≥7, PSA ≥20 ng/mL) in an affected man.[5-7] 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.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]Candidate genes and susceptibility loci identified in linkage analyses
Refer to the HOXB13 section in the Genes with Potential Clinical Relevance in Prostate Cancer Risk section of this summary.Additional prostate cancer susceptibility loci identified in linkage analyses
Table 7 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 described above. Data on the proposed phenotype associated with each locus are also limited, 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.Table 7. Proposed Prostate Cancer Susceptibility Loci
|Gene||Location||Candidate Gene||Clinical Testing||Proposed Phenotype||Comments|
|HPC1 (OMIM)/RNASEL (OMIM) [12-33]||1q25||RNASEL||Not available||Younger age at prostate cancer diagnosis (<65 y)||Evidence of linkage is strongest in families with at least five affected persons, young age at diagnosis, and male-to-male transmission.|
|Higher tumor grade (Gleason score)|
|More advanced stage at diagnosis||RNASEL mutations have been identified in a few 1q-linked families.|
|PCAP (OMIM) [1,9,16,23,34-43]||1q42.2–43||None||Not available||Younger age at prostate cancer diagnosis (<65 y) and more aggressive disease||Evidence of linkage is strongest in European families.|
|HPCX (OMIM) [33,38,44-50]||Xq27–28||None||Not available||Unknown||May explain observation that an unaffected man with an affected brother has a higher risk than an unaffected man with an affected father.|
|CAPB (OMIM) [36,51-53]||1p36||None||Not available||Younger age at prostate cancer diagnosis (<65 y)||Strongest evidence of linkage was initially described in families with both prostate and brain cancer; follow-up studies indicate that this locus may be associated specifically with early-onset prostate cancer but not necessarily with brain cancer.|
|One or more cases of brain cancer|
|HPC20 (OMIM) [38,54-57]||20q13||None||Not available||Later age at prostate cancer diagnosis||Evidence of linkage is strongest in families with late age at diagnosis, fewer affected family members, and no male-to-male transmission.|
|No male-to-male transmission|
|8p [23,39,58-66]||8p21–23||MSR1||Not available||Unknown||In a genomic region commonly deleted in prostate cancer.|
|8q [43,67-84,84-86]||8q24||None||Not available||More aggressive disease||Data in some reports suggest that the population-attributable risk may be higher for African American men than for men of European origin.|
Other regions identified by linkage studies
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 (logarithm of the odds [LOD] score ≥2) include the following chromosomes:
- 2q35 
- 2q37 
- 3p14 [88-90]
- 3p24-26 [41,43,91-93]
- 4q22.1 
- 5q11-12 [42,92]
- 5q35 [92,94]
- 6p22.3 [39,95]
- 7q32 [9,39,94,96]
- 8p11.21 
- 8q13 [92,97]
- 9q34 [9,23]
- 11q22 [92,98]
- 12q23.2 
- 12q24.31 
- 13q12.13 
- 13q34 
- 15q11 [92,99]
- 15q14 
- 16p12.1 
- 16q23 [9,100]
- 17q21-22 [40,77,87,92,99,101-104]
- 19q [8,11,94]
- 22q12.3 [5,92,98,105-108]
Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.Linkage analysis in African American families
The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint heterogeneity LOD (hLOD) scores of 1.3 to 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 = 1.08) and 22q12 (multipoint hLOD score = 0.91).[92,98] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (hLOD = 1.97) and 12q24 (hLOD = 2.21) using a 6,000 SNP platform. Further study including a larger number of African American families is needed to confirm these findings.Linkage analysis in families with aggressive prostate cancer
In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer < before age 65 years. 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 = 2.18) and 22q12.3-q13.1 (hLOD score = 1.90). 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. An analysis of high-risk pedigrees from Utah provides an overview of this strategy. A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer. Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.09–3.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.Linkage analysis in families with multiple cancers
In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic. 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 and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2. This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 HPC families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.Summary of prostate cancer linkage studies
Linkage to chromosome 17q21-22 and subsequent fine-mapping and exome sequencing have identified recurrent mutations in the HOXB13 gene to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility of testing for HOXB13 mutations has not yet been defined. Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table ), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.Case-Control Studies
A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[113,114]
- Stratification of the population being studied. (Unknown population based genetic differences between cases and controls that could result in false positive associations.)
- Genetic heterogeneity. (Different alleles or loci that can result in a similar phenotype.)
- Limitations of self-identified race or ethnicity and unknown confounding variables.
Refer to the BRCA1 and BRCA2 section in the Genes with Potential Clinical Relevance in Prostate Cancer Risk section of this summary.EMSY
The EMSY gene is located on chromosomal locus 11q13.5 and is in an area of both linkage and association by genome-wide association studies (GWAS).[41,116] This gene has also been shown to interact with and inhibit the activity of BRCA2. A study from Finland screened the EMSY gene for sequence variants and evaluated their association with prostate cancer risk in a population-based case-control study including 923 controls, 184 familial cases, and 2,301 unselected prostate cancer cases. An intronic variant (IVS6-43A>G) was associated with increased risk of prostate cancer in familial cases (OR, 7.5; 95% CI, 1.3–45.5; P = .02). This variant was also associated with increased risk of aggressive prostate cancer (PSA ≥20 or Gleason score ≥7) in cases unselected for family history (OR, 6.5; 95% CI, 1.5–28.4; P = .002). Validation of this finding with association to other measures of disease aggressiveness (e.g., prostate cancer–specific mortality) is needed. The functional consequence of this intronic variant also needs to be explored for insight into the role of this gene in susceptibility to aggressive disease.Mismatch repair genes
Refer to the Mismatch Repair Genes section in the Genes with Potential Clinical Relevance in Prostate Cancer Risk section of this summary.KLF6
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. 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. 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. 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; 95% CI, 1.20–2.16; P = .01). However, the prostate cancer risk associated with the IVS1-27G>A SNP was not detected in a study of 300 Jewish prostate cancer families. 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 the Israeli study (49 of 804 alleles in cases and 55 of 600 control alleles; P = .030).AMACR
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. 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 participated in a research study focused on early-onset prostate cancer and/or HPC. An association was found for SNP rs3195676 (M9V) with an OR of 0.58 (95% CI, 0.38–0.90, P = .01 for a recessive model). The reported magnitude and direction of the association observed for this SNP were similar among this study and previously mentioned AMACR resequencing experiments. A nested case-control study was conducted using samples from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO-1) to test for potential association between seven AMACR SNPs , including M9V, and prostate cancer. No association was detected between any of the SNPs and prostate cancer. The prostate cancer cases in the PLCO study are all older than 55 years and not specifically enriched for family history. In the same study, risk of prostate cancer was reduced in men who reported using ibuprofen who also had specific alleles in four 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.Other potential prostate cancer genes
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. 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  and ataxia telangiectasia.[128,129] 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. A collaborative report from five groups participating in the International Consortium for Prostate Cancer Genetics 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.CHEK2
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. 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 reported 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.[131,132] 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. 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 and 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. However, a recent molecular analysis designed specifically to assess the role of seven different CHEK2 coding variants (including 1100delC) in AJ 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 AJ men. This conclusion is limited by the relatively small number of individuals in whom CHEK2 sequencing was performed.
Table 8 summarizes the candidate genes for prostate cancer susceptibility, their chromosomal location, and availability of clinical testing.Table 8. Candidate Genes for Prostate Cancer Susceptibility
|Gene||Location||Clinical Testing||Proposed Phenotype||Comments|
|HPC = hereditary prostate cancer; MMR = mismatch repair; OMIM = Online Mendelian Inheritance in Man.|
|AMACR (OMIM) [123-125]||5p13.2||Not available||Unknown|
|BRCA1 (OMIM) [136-146]||17q21||Available||Younger age at prostate cancer diagnosis (<65 y); earlier age at diagnosis among carriers of Ashkenazi founder mutations||There is some evidence that men with a BRCA1 mutation may develop prostate cancer at an earlier age.|
|BRCA2 (OMIM) [138-142,144,145,147-152]||13q12-13||Available||Younger age at prostate cancer diagnosis (<65 y); earlier age at diagnosis among carriers of Ashkenazi founder mutations||Evidence for an increase in prostate cancer risk is stronger for BRCA2 than BRCA1. Individuals with BRCA2-related prostate cancer have significantly worse survival rates than noncarriers due to higher Gleason scores and more advanced tumor stage at diagnosis. Prostate cancer risk may be lower among men with a mutation in the central region of the BRCA2 gene.|
|CHEK2 (OMIM) [131,133,134]||22q12.1||Available||Unknown||Value of clinical testing for mutations in CHEK2 for prostate cancer risk is not established.|
|ELAC2/HPC2 (OMIM) [31,153-158]||17p||Not available||Unknown||Infrequent deleterious mutations identified in HPC families in follow-up reports.|
|HOXB13 (OMIM) ||17q21||Not available||Younger age at prostate cancer diagnosis (≤55 y) and a positive family history of prostate cancer|
|KLF6 (OMIM) [119-122,160]||10p15||Not available||Younger age at prostate cancer diagnosis (<65 y)|
|MMR Genes: MLH1 (OMIM), MSH2 (OMIM), MSH6 (OMIM), or PMS2 (OMIM) [161,162]||3p21.3, 2p22-p21, 2p16, 7p22||Available||Unknown||Prostate cancers due to MMR gene mutations have been shown to have evidence of microsatellite instability.|
|MSR1 (OMIM) [31,59,60,65,122]||8p22||Not available||Unknown||In a genomic region commonly deleted in prostate cancer.|
|NBS1 (OMIM) [126,130]||8q21||Available||Increased prostate cancer risk in heterozygotes||Infrequent NBS1 mutations, including founder 657del5 variant, in follow-up study.|
To summarize, studies to date have mapped site-specific prostate cancer susceptibility loci to chromosomes 1q25 (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 later-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 with their associated phenotype defined, 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 most HPC susceptibility loci is not available. In addition, the clinical validity and utility of BRCA testing solely based on evidence for HPC susceptibility has not been established.Other Regions Identified by Admixture Studies
Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases that controls for population composition associated with geographically distinct ancestral groups. This approach is used when admixture occurred two or more generations ago. It is based on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[164,165] The advantage to this approach is that recent mixtures of distinct ancestral populations may have longer-range linkage disequilibrium between susceptibility alleles and genetic markers when compared with other populations. In that scenario, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:Genome-wide Association Studies (GWAS)
- GWAS can identify inherited genetic variants that influence risk of disease.
- For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
- To date, GWAS have discovered dozens of genetic variants associated with prostate cancer risk.
- Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information contributes substantially to variables commonly used to assess risk, such as family history.
Genome-wide searches are showing great promise in identifying common low-penetrance susceptibility alleles for many complex diseases, including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants cosegregating within families that have a high prevalence of disease. While linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial), GWAS are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given population (e.g., men of European ancestry). GWAS capture a large portion of common variation across the genome.[169,170] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to “scan” the genome without having to test all 10 million known single nucleotide polymorphisms (SNPs). GWAS can test 500,000 to 1,000,000 SNPs and ascertain almost all common inherited variants in the genome.
In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signals–in which allele frequencies deviate significantly in case and control populations–are validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Since up to 1 million SNPs are evaluated in a GWAS, false-positive findings are expected to occur frequently when using standard statistical thresholds. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 × 10-7.[171-173]
To date, approximately 40 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 9). These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:
- GWAS reported thus far have been designed to identify relatively common genetic polymorphisms. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of prostate tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an odds ratio (OR) for disease risk of less than 1.5. In addition, despite extensive genome-wide interrogation of common polymorphisms in tens of thousands of cases and controls, GWAS findings to date do not account for even half of the genetic component of prostate cancer risk.
- Variants uncovered by GWAS are not likely to be the ones directly contributing to disease risk. As mentioned above, SNPs exist in linkage disequilibrium blocks and are merely proxies for a set of variants—both known and previously undiscovered—within a given block. The causal allele is located somewhere within that linkage disequilibrium block.
- Admixture by groups of different ancestry can confound GWAS findings (i.e., a statistically significant finding could reflect a disproportionate number of subjects in the cases versus controls, rather than a true association with disease). Therefore, GWAS subjects, by design, comprise only one ancestral group. As a result, many populations remain underrepresented in genome-wide analyses–notably African Americans, whose risk of prostate cancer is among the highest in the world.
The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.Candidate genes and susceptibility loci identified in GWAS
In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men. In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus. Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737. The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%. These results were confirmed in several large, independent cohorts.[69-72,79-82,176] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[72-74] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54–128.62 Mb, region 2 at 128.14–128.28 Mb, and region 3 (containing rs6983267) at 128.47–128.54 Mb. Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[85,86]
Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for the European-American population are included in Table 9.Table 9. Prostate Cancer Susceptibility Loci Identified Through GWAS
|Nearest Known Gene Within 100 kb||Chromosomal Locus||SNP||Region||Study Citations||ORa|
|GWAS = genome-wide association studies; kb = kilobase; OR = odds ratio.|
|aORs are reported as a range across the various stages of GWAS discovery and validation when available.|
Clinical application of GWAS findings
Since the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region. Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 × 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.93–6.80; P = 1.20 × 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.62–24.72; P = 1.29 × 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.
A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.64–6.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.83–5.33).
However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected. The addition of more recently discovered SNPs to the model has not appreciably improved these results. While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.
Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.
In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS. Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have “poor discriminative ability” to identify individuals at risk of developing the disease.
GWAS findings to date account for only a fraction of heritable risk of disease. Future work will likely uncover most of the remaining portion of genetic risk. More risk alleles will be discovered, including rarer alleles with higher ORs. In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.GWAS and insight into the mechanism of prostate cancer risk
Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:
- Risk alleles discovered by GWAS are in linkage disequilibrium with exonic variants that directly influence gene products.
- Risk alleles do in fact reside in areas of transcription, but transcription at these sites has not yet been annotated.
- Risk alleles reside within regulatory elements and genotype within these areas influence activity of distal genes.
The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci. Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[190-192] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC. Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[191,193] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.GWAS in non-European populations
Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups. Most work in this regard has focused on African American and Japanese men.
The African American population is of particular interest since American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease. A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls. On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P ≤ .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.
This analysis was followed by a GWAS to discover risk variants not previously identified in GWAS performed in other ethnicities. The GWAS was conducted in a standard multistage fashion in which 3,621 African American cases and 3,502 controls were genotyped for approximately 1 million SNPs. SNPs meeting proscribed statistical thresholds were selected for a second stage in 1,396 cases and 2,383 controls (known prostate cancer risk SNPs were excluded, as they had been rigorously analyzed, as described above). One marker–rs7210100 at chromosome 17q21–emerged and remained significant when tested in a third stage with 3,471 cases and 904 controls. When combining cases and controls from all three stages, prostate cancer risk in heterozygote and homozygote carriers of the rs7210100 risk allele was 1.49 and 2.73, respectively (P = 3.4 × 10-13). The risk allele is uncommon in African Americans (4%–7% frequency) but is virtually nonexistent in men of European ancestry. The SNP may therefore account for some ethnic difference in risk. It resides in intron 1 on the gene ZNF652. Co-expression of ZNF652 and the androgen receptor in prostate tumors has been associated with a decrease in relapse-free survival, which may suggest a mechanism of action if this variant influences expression.
A case-control study evaluated GWAS-identified prostate cancer–associated genetic markers at chromosomal region 8q24 in men of African ancestry in Tobago, Republic of Trinidad and Tobago. Among 354 cases and 438 controls, rs16901979 was significantly associated with prostate cancer risk (OR, 1.41; 95% CI, 1.02–1.95; P = .04), with higher associated risk in men with early-onset prostate cancer (OR, 2.37; 95% CI, 1.40–3.99; P = .001).
Similar work has been accomplished in the Japanese population. Twenty-three candidate SNPs related to prostate cancer risk in two GWAS studies of European populations were evaluated in a relatively small population of Japanese cases (n = 311) and controls (n = 1,035). Seven of these SNPs (from five genetic loci) were associated with prostate cancer risk (OR, 1.35–1.82). Men with six or more risk alleles (27% of cases and 11% of controls) had a sixfold greater prostate cancer risk than those with two or fewer risk alleles (7% of cases and 20% of controls [OR, 6.22; P = 1.5 × 10-12]). To further assess susceptibility loci in a Japanese population, a two-stage GWAS was conducted using a total of 4,584 Japanese men with prostate cancer and 8,801 controls. The study resulted in the identification of five SNPs from five separate loci not previously associated with prostate cancer: rs13385191 at 2p24 (OR, 1.15); rs12653946 at 5p15 (OR, 1.26); rs1983891 at 6p21 (OR, 1.15); rs339331 at 6q22 (OR, 1.22); and rs9600079 at 13q22 (OR, 1.18) [data after combining cohorts from both stages of the study]. A set of nine SNPs that were nominally associated with disease risk in the initial GWAS were subsequently analyzed in other large Japanese cohorts and then united with the original cases and controls in a meta-analysis (7,141 prostate cancer cases and 11,804 controls). This study revealed three new prostate cancer risk loci in this ancestral population: rs1938781 at 11q12 (OR, 1.16); rs2252004 at 10q26 (OR, 1.16); and rs2055109 at 3p11.2 (OR, 1.20).
These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.Conclusions
Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project. Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.Genetic Modifiers of Prostate Cancer Aggressiveness
Due to the screening-related debate over risk of identifying clinically insignificant prostate cancers and the potential for overtreatment, studies characterizing genetic variants in subsets of patients with aggressive disease (e.g., Gleason score ≥8) are now being reported.
One study evaluated the association between the CASP8 D302H polymorphism and aggressive prostate cancer in a pooled analysis from three studies including 796 aggressive prostate cancer cases and 2,060 controls. Aggressive disease was defined as having androgen ablation therapy for prostate cancer, a PSA level greater than 50 ng/mL, radiographic evidence of metastases, or a Gleason score of 8 to 10. The H allele was associated with a protective effect for aggressive prostate cancer (OR per allele, 0.67; 95% CI, 0.54–0.83, P = .0003). The results were similar for European Americans and African Americans. The protective effect was observed only for aggressive disease, not for prostate cancer risk overall or for indolent prostate cancer, implying potential utility in identifying patients at risk of clinically significant disease.
A second study focused on germline polymorphisms residing in the gene C-C chemokine ligand 2 (CCL2). This gene appears to play a role in prostate cancer tumorigenesis and invasion. In a cohort of 4,073 European American men with prostate cancer, inheriting the CCL2 -1181 G allele (AG or GG genotype) was associated with advanced pathologic stage (OR, 1.50; 95% CI, 1.03–2.18; P = .04) and higher Gleason score (OR, 1.47; 95% CI, 1.08–2.01; P = .01), compared with the AA genotype.
Twenty prostate cancer risk SNPs identified in GWAS and fine-mapping follow-up studies were evaluated in 5,895 prostate cancer patients in search of SNP associations with prostate cancer aggressiveness. The risk-associated alleles of two SNPs (rs2735839 in KLK3 and rs10993994 in MSMB) were significantly associated with less aggressive prostate cancer; no significant associations were observed for the other 18 candidate SNPs. Similarly, in a larger cohort from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium that included 10,501 prostate cancer cases and 10,831 controls, the rs2735839 risk allele was associated with less aggressive disease. The two SNPs are known to be associated with PSA levels in normal men without prostate cancer. The authors concluded that the observed associations may be driven by over-representation within their case series of PSA screen-detected low-grade/low-stage disease and that none of these risk-related SNPs appear to hold the potential for identifying men at increased genetic risk of more aggressive prostate cancer.
A single institution study evaluated 36 SNPs for association with disease aggressiveness and prostate cancer–specific mortality in a prostate cancer cohort including 3,945 cases (predominantly European ancestry) and 580 prostate cancer–specific deaths. Two SNPs were associated with prostate cancer–specific survival (rs2735839 at 19q13, P = 7 × 10-4 and rs7679673 at 4q24, P = .014). Twelve SNPs were associated (P < .05) with other measures of prostate cancer aggressiveness, including age at diagnosis, PSA level at diagnosis, Gleason score, and D’Amico criteria. These results need confirmation, as adjustment for multiple testing was not performed and ascertainment bias from single institution referral and screening patterns may have influenced the findings.
Interestingly, in the retrospective series above, the prostate cancer risk allele at rs2735839 was associated with lower PSA levels and less aggressive disease.[180,207] A hypothesis explaining this phenomenon is that those carrying the allele associated with aggressiveness generally have lower PSAs, are sent for prostate biopsy less often, and are diagnosed later in the natural history of the disease.
One study evaluated the risk of metastatic prostate cancer (470 incident metastatic prostate cancer cases and 1,945 controls) and prostate cancer recurrence after prostatectomy for localized disease (1,412 localized prostate cancer cases, 328 of which had recurrence) with 12 SNPs previously found to be associated with prostate cancer risk. The T allele of rs10993994 in MSMB was associated with increased metastatic prostate cancer risk (RR, 1.24; 95% CI, 1.05–1.48; P = .012). The authors hypothesize that this SNP could be associated with primary carcinogenesis because metastatic prostate cancer at the time of diagnosis is less likely to be associated with PSA screen–detected disease. The other significant finding was the association in 8q24 of the A allele of rs4242382 (RR, 1.40; 95% CI, 1.13–1.75) and inverse association of the T allele of rs6938267 (RR, 0.67; 95% CI, 0.50–0.89) with metastatic prostate cancer. None of the SNPs studied were associated with risk of recurrence. These findings were not consistent with results of similar retrospective series.[205,209]
The association between prostate cancer–specific mortality (PCSM) and 846 SNPs was studied in a population-based prostate cancer cohort of 1,309 individuals in Seattle. Twenty-two SNPs found to be significantly associated with PCSM were then studied in a validation cohort of 2,875 prostate cancer cases from Sweden, of which five SNPs were significantly associated with PCSM. Hazard ratios in the Swedish validation cohort after adjusting for age at diagnosis, Gleason score, stage, PSA at diagnosis, and treatment for three of the SNPs were as follows: rs1137100 (LEPR) (HR, 0.82; 95% CI, 0.67–1.00; P = .027); rs2070874 (IL4) (HR, 1.27; 95% CI, 1.04–1.56, P = .011); and rs10778534 (CRY1) (HR, 1.23; 95% CI, 1.00–1.51, P = .022). Two of the SNPs were validated after adjusting for age at diagnosis alone: rs627839 (RNASEL) (HR, 1.22; 95% CI, 1.00–1.50, P = .024) and rs5993891 (ARVCF) (HR, 0.72; 95% CI, 0.52–1.01, P = .024). Compared with patients with zero to two at-risk genotypes, there was an increase in risk observed in patients with a greater number of at-risk genotypes after adjusting for age at diagnosis, Gleason score, stage, PSA at diagnosis, and treatment as follows: three at-risk genotypes (HR, 1.05; 95% CI 0.81–1.37); four at-risk genotypes (HR, 1.51; 95% CI, 1.16–1.97); and five at-risk genotypes (HR, 1.46 95% CI, 0.97–2.19). These results need validation for informing patient risk assessment and management.
To definitively identify the inherited variants associated with prostate cancer aggressiveness, well-powered GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. The control arm of such a study could be comprised of age-matched controls with no evidence of the disease or men with low-grade, indolent disease. One underpowered study genotyped 202 aggressive cases and 100 men matched by PSA and age who had not developed the disease using a SNP panel of 387,384 polymorphisms. Results were validated in a cohort of 527 aggressive cases, 595 less-aggressive cases, and 1,167 controls. The GWAS produced one SNP, rs6497287 at chromosome 15q13, as associated with aggressive disease. These results require further validation but point to the potential for GWAS focusing on this important phenotype.References
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