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Prostate cancer is the second leading cause of cancer-related deaths in men in the USA . Men with a family history of prostate cancer and African-American men are considered to be at high-risk for prostate cancer [1-4], with subsets being at greater risk for younger age at diagnosis and aggressive disease [5-10]. Given these factors, men in the high-risk group, in particular, stand to benefit from optimized prostate cancer screening approaches.
PSA-based methods for prostate cancer screening remain controversial for the general population because of a lack of consistency in reducing mortality and the estimated number needed to screen to prevent a prostate cancer death [11-14]. There is concern about early detection leading to overdiagnosis and overtreatment of indolent prostate cancer, and standard therapy may result in significant morbidity and negative impacts on urinary, bowel and sexual function . Furthermore, PSA may show false-positive elevations, leading to unnecessary testing and prostate biopsies, which have the potential for serious complications , and yet, prostate cancer detection has been reported even at PSA values <3.0 ng/mL [6, 7, 17]. Based on these studies, several national organizations have offered a range of recommendations regarding PSA-based screening for prostate cancer. The US Preventative Services Task Force recently recommended against routine PSA testing for men at any age unless they have symptoms of prostate cancer, stating that the harms resulting from screening outweigh the potential benefits . The American Cancer Society advocates that patients and doctors engage in informed and shared decision-making regarding PSA testing for prostate cancer screening, and further recommends that men in the high-risk group have this discussion at age 45 years . The AUA recommends that men under age 55 years with a family history of prostate cancer or African American men make individualized screening decisions . In addition, the American Society of Clinical Oncology issued a provisional opinion that clinicians should discuss the benefits and potential harms of PSA-based screening for prostate cancer in men with a life expectancy >10 years . They also stressed the importance of shared decision-making between patients and providers. There is a need, therefore, to develop approaches to optimize risk assessment for prostate cancer, particularly for men in the high-risk group, and one approach is to individualize the interpretation of PSA levels to make appropriately informed prostate cancer screening recommendations.
Genetic variation has been reported to be associated with PSA levels, with potential implications for adjustment of PSA level based on genotype. A previous genome-wide association study for prostate cancer reported the association of multiple genetic variants, particularly on chromosomes 10 and 19, with PSA levels . A subsequent study from the Baltimore Longitudinal Study of Aging reported the association of genetic variants on chromosomes 10 and 19 with prostate cancer risk at specific PSA levels, suggesting that genotypes could improve on the PSA test for prostate cancer risk stratification . In 2010, Gudmundsson et al.  reported findings from a PSA-focused genome-wide association study and identified six genetic variants associated with PSA, primarily in Caucasian men at average risk. An additional goal of this previous study was to develop individualized PSA thresholds, based on genetic variation, to guide recommendations for prostate biopsy. Other studies have evaluated the use of single nucleotide polymorphisms (SNPs) in prostate cancer screening, with conflicting results. One study reported a marginal benefit to adding 33 prostate cancer-associated SNPs to PSA level , while another study reported that four genetic variants can be useful in correcting PSA, leading to a reduction in unnecessary prostate biopsies . These previous studies primarily included Caucasian men at average risk for prostate cancer. Since men with a family history of prostate cancer and African-American men are considered to be at high risk for developing prostate cancer and are in need of personalized screening recommendations, candidate genetic variants deserve further study for PSA association and potential adjustment of PSA, particularly in this high-risk population who may benefit.
The present study was performed to validate the findings of the association of six genetic variants previously found to be associated with PSA levels  in a high-risk, ethnically diverse cohort of men undergoing prostate cancer screening in the Prostate Cancer Risk Assessment Program (PRAP) . As men in the high-risk group are at greater risk for a diagnosis of prostate cancer, particularly at younger ages [6, 7], PRAP was an ideal, diverse cohort in which to study candidate genetic variants for association with PSA levels and to develop adjustments to PSA level based on genetic information particularly relevant to men in the high-risk group.
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At the time of this analysis, 740 participants were accrued to PRAP, and the primary analysis of six candidate genetic variants and association with PSA levels included 707 PRAP participants with complete clinical, demographic and genotype data available. Exclusions from the analysis included men of self-identified race other than Caucasian or African-American (N = 8), African-American men with any undetermined genotypes (N = 19), and Caucasian men with any undetermined genotypes (N = 6). Table 1 describes the characteristics of these 707 participants by self-reported race. As can be seen in Table 1, the mean age at entry into PRAP was similar by race, with African-American participants at 49.6 years and Caucasian participants at 50.1 years. The mean PSA level at entry for African-American men was 1.67 ng/mL and for Caucasian participants it was 1.70 ng/mL. The mean PSA level before diagnosis was identical for both race groups at 3.4 ng/mL. There was a significant difference noted in the percentage of men with any follow-up, with a greater percentage of Caucasian men with follow-up than African-American men (80 vs 59%; P < 0.01). No other significant differences were observed between race groups. Table 2 shows the allele frequencies of the six candidate genetic variants evaluated in this analysis. Significant differences were observed in candidate allele frequencies by self-reported race. No differences were observed on Hardy–Weinberg equilibrium tests.
Table 1. Demographic and prostate cancer characteristics of 707 PRAP participants, stratified by self-reported race
| ||African-American men, N = 447||Caucasian men, N = 260|
|Mean (range) age at entry, years||49.6 (35–69)||50.1 (35–69)|
|Family history of prostate cancer, n (%)||144 (32.2)||255* (98.1)|
|Mean (range) duration of follow-up, months|| || |
|PSA at baseline (ng/mL)|| || |
|DRE at baseline, n (%)|| || |
|Normal/BPH||425 (95.9)||244 (95.7)|
|Abnormal||18 (4.1)||11 (4.3)|
|Number participants biopsied after enrolment into PRAP, n (%)||96 (21.5)||78 (30)|
|Prostate cancer diagnosis, n (%)||44 (9.8)||39 (15.0)|
|Mean (range) age at diagnosis, years|| || |
|Mean (range) last PSA level before diagnosis, ng/mL|| || |
|Mean (range) Gleason score|| || |
Table 2. Allele frequencies, stratified by race
|Chromosome||SNP||Risk allele*||Caucasian men||African-American men||Test for allele frequency differences by race|
|RAF||Number of participants with genotypes||RAF||Number of participants with genotypes||Chi-squared||Chi-squared P|
|5||rs2736098||T||0.26||257||0.11||438||68.05||1.59 × 10−16|
|10||rs10993994||T||0.43||258||0.63||428||51.95||5.69 × 10−13|
|10||rs10788160||A||0.27||242||0.06||381||109.01||1.61 × 10−25|
|12||rs11067228||A||0.54||256||0.81||441||115.86||5.10 × 10−27|
|17||rs4430796||A||0.53||237||0.33||427||54.42||1.62 × 10−13|
|19||rs17632542||T||0.93||255||0.98||442||28.04||1.19 × 10−7|
Table 3 shows the results of the association analyses between the candidate variants and PSA levels by self-reported race. rs10788160 at 10q26 was strongly associated with PSA levels among Caucasian PRAP participants, of whom 98% had a family history of prostate cancer (P < 0.01), with a 33.2% increase in PSA level with each A-allele carried. The association of rs10788160 with PSA levels was not as strong among African-American PRAP participants (P = 0.02), with significance disappearing after correcting for false-discovery rate. Among Caucasian participants, rs10993994 (10q11) was found to be associated with PSA level (P = 0.03). Thisassociation dissipated somewhat after correction for false discovery (false-discovery corrected: P = 0.09), with a 15% increase in PSA level with each T-allele carried. No association was observed with PSA levels among African-American PRAP participants for rs10993994. In addition, no significant associations with prostate cancer were observed for the six candidate variants in the PRAP cohort, although sample sizes for these comparisons were small (Table S1).
Table 3. Association of candidate SNPs with PSA levels at baseline in 707 PRAP participants by self-reported race, adjusted for age at entry
| ||Chromosomal locus||SNP||Risk allele*||Number of men with genotype||%PSA change per allele||P||FDR-corrected P-value†|
|Caucasian (N = 260)||5p15.33||rs2736098||T||256||−8.1||0.25||0.30|
|African Americans (N = 447)||5p15.33||rs2736098||T||434||2.8||0.76||0.76|
Since rs10788160 and rs10993994 had the strongest associations with PSA level among Caucasian PRAP participants, these two markers were incorporated into a genetically based PSA-adjustment model as per Gudmundsson et al. . Table 4 shows the suggested PSA thresholds in Caucasian men in the high-risk group at which, after further confirmation, one could consider further clinical evaluation (such as more frequent PSA checks or a biopsy). For example, using this model, a Caucasian male with a family history of prostate cancer with no PSA-associated alleles at rs10788160 and rs10993994 could be considered for further evaluation when the PSA level was 2.97 ng/mL rather than 4.0 ng/mL. Conversely, if the same patient carries all four alleles, then further evaluation could be delayed until a PSA level of 6.96 ng/mL was reached; thus, the PSA level may be interpreted on an individual basis for recommending further evaluations and sparing unnecessary biopsies and testing upon further confirmation.
Table 4. Proposed genotype-adjusted PSA thresholds for Caucasian PRAP participants
| ||Proposed adjusted PSA threshold for biopsy, ng/mL|
|Genotype combination (number of PSA-increasing alleles)|| |
|rs10788160 (0)/ rs10993994 (0)||2.97|
|rs10788160 (0)/ rs10993994 (1)||3.42|
|rs10788160 (0)/ rs10993994 (2)||3.93|
|rs10788160 (1)/ rs10993994 (0)||3.96|
|rs10788160 (1)/ rs10993994 (1)||4.55|
|rs10788160 (1)/ rs10993994 (2)||5.23|
|rs10788160 (2)/ rs10993994 (0)||5.26|
|rs10788160 (2)/ rs10993994 (1)||6.05|
|rs10788160 (2)/ rs10993994 (2)||6.96|
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Risk assessment for prostate cancer is currently in evolution, with one main challenge being the controversy over PSA-based screening for the disease in the general population [11-14]. Yet men with familial prostate cancer and African-American men are both considered to be at high risk for prostate cancer [1-4], and subsets have been found to develop aggressive disease and ultimately die from prostate cancer [5-10]. Most experts agree that the downstream impact of PSA-based screening is the key concern, with risk for overdiagnosis of indolent prostate cancer, overtreatment with exposure to risks and side effects, and unnecessary biopsies with risks of bleeding, infection and potentially sepsis. The appropriate interpretation of PSA level, on an individual basis, holds promise for informing patients and providers when making decisions for prostate cancer screening, especially in individuals who have a greater than average risk for the development of prostate cancer. Thus, efforts have begun to identify factors that affect the significance and interpretation of PSA levels.
Previous studies have shown genomic variants to be associated with PSA levels, primarily in Caucasian men at average risk for prostate cancer [23-25]. In 2010, Gudmundsson et al. identified six genetic variants associated with PSA levels from a PSA-focused genome-wide association study in primarily average risk Caucasian men and proposed genetically adjusted PSA thresholds . Since men with a family history of prostate cancer and African-American men are in need of strategies to individualize the interpretation of PSA level, we aimed to validate these previous SNP associations in an ethnically diverse cohort of men, all at high-risk for prostate cancer, to gain insight into the potential role of six of these variants in prostate cancer risk assessment, specifically for this high-risk population. We validated the association of two markers at 10q (rs10788160 at 10q26 and rs10993994 at 10q11) with PSA levels among Caucasian men with a family history of prostate cancer and we propose a genetically based adjustment to PSA interpretation specific to Caucasian men in the high risk group. To our knowledge, this is the first report of genetic impact on interpretation of PSA specifically among high-risk Caucasian men.
Among Caucasian men enrolled in PRAP, rs10788160 at 10q26 had the strongest association with PSA levels, with the greatest increase in PSA per risk allele, which confirms previous findings from a PSA-focused genome-wide association study . This variant was not previously reported to be associated with prostate cancer, and therefore this variant may prove to be more useful in adjusting PSA level, particularly among Caucasian men with a family history of prostate cancer, and thereby avoiding unnecessary prostate biopsies. Marker rs10993994 at 10q11 had a weaker association with PSA levels among Caucasian men at high risk in our cohort. This variant has previously been reported to be associated with prostate cancer [31-33] and PSA levels [22-24, 34]. Rs10993994 is close to the transcription start site of MSMB, and the T-allele of rs10993994 has been reported to be associated with lower transcript levels and expression of MSMB in normal and tumour prostate tissues . It is noted that discerning the effect of rs10993994 on PSA levels vs prostate cancer is challenging. A previous study did not include this marker in their genetic correction model for PSA adjustment . We chose to include rs10993994 in our genetic correction model for Caucasian men at high risk as no association with prostate cancer was found in the present study. It is noted that other studies have reported the association of rs10993994 with prostate cancer but not with aggressive disease, to our knowledge ; thus, if rs10993994 is associated with PSA level and/or with less aggressive prostate cancer, correction of PSA by including this marker may limit unnecessary biopsies in patients, some of whom may have indolent prostate cancer. Further study is needed to confirm our findings and characterize the influence of rs10788160 and rs10993994 in prostate cancer biology.
The present study has some limitations. Four of the six previously reported variants were not associated with PSA levels in our cohort, which may have been attributable to sample size. A larger study confirming our findings among men at high risk is warranted. We observed a modest association of rs10788160 with PSA levels among African-American PRAP participants, which disappeared after correction for false discovery. None of the other variants were observed to be associated with PSA levels in African-American men in the PRAP, which may be because of sample size and/or race-specific genetic variation influencing PSA levels. Further study is needed in larger cohorts of men of African descent to study the genetic influence on PSA levels. In addition, as SNP prevalence differs by race, there may be inherent limitations in detecting SNP associations with PSA level, either among Caucasian or African-American men in the PRAP cohort.
In summary, the present study found that allelic variation of two genetic polymorphisms at 10q, namely, rs10788160 (10q26) and rs10993994 (10q11), may be of particular importance in the interpretation of PSA level for Caucasian men with a family history of prostate cancer. Given the current controversy over the benefits vs the risks of PSA-based screening for prostate cancer, individualized interpretation of PSA holds promise for informing discussions of prostate cancer risk assessment and ultimately to identify clinically meaningful prostate cancer while minimizing harm. Men with familial risk for prostate cancer, and African-American men in particular, stand to benefit from such research.