Despite recent studies documenting a significant reduction in prostate cancer specific mortality in the prostate specific antigen (PSA) screening era, the PSA test continues to undergo tremendous scrutiny. For example, PSA testing has been associated with ‘unnecessary’ biopsies and the overtreatment of seemingly ‘indolent’ prostate tumours. Furthermore, treatment for these nonlife-threatening tumours has been associated with both significant financial cost and potential side-effects, including erectile dysfunction, incontinence and bowel issues [1–3]. Because of the lack of consensus weighing the mortality benefits against the harms of biopsy and treatment, the US Preventive Services Task Force (USPSTF) finalized its recommendations against all PSA screening in May 2012 . Similarly, the American Urologic Association (AUA) recently recommended for targeted PSA screening for men at elevated risk, rather than mass testing . Thus, there is a need for new biomarkers that can better distinguish men who are likely to harbour prostate cancer and particularly which men are likely to develop aggressive disease. Identification and incorporation of these biomarkers into clinical practice offers the potential for significant improvements in prostate cancer screening and treatment.
In addition, to age and race, a positive family history of the disease is one of the strongest risk factors for developing prostate cancer [6–8]. Specifically, it has been demonstrated that a family history of prostate cancer increases the relative risk up to 2.50-fold . In addition, it has been shown that the risk for being diagnosed with prostate cancer is higher amongst men with affected first-degree relatives (father, brothers, sons) than in second-degree relatives; these risks were estimated to be 2.22 [95% confidence interval (95% CI) 2.06–2.40] and 1.88 (95% CI 1.54–2.30), respectively . Studies of over 44 000 twin pairs has shown that the concordance rates of prostate cancer are 21 and 6% in monozygotic and dizygotic twins, respectively. On the basis of this, it was estimated that up to 42% of disease risk could be explained by genetic factors alone . Finally, some reports suggest that family history may also contribute to increased prostate cancer specific mortality .
Despite this large genetic component, the study of cancer genetics has been unable to identify a single genetic mutation that explains prostate cancer risk in the majority of men. However, over the past several decades, genetic researchers have witnessed a revolution in technologic advances that have provided more efficient and cost-effective ways to perform genetic sequencing. These advances have allowed for the identification of common genetic variants in germline DNA that are associated with significantly increased prostate cancer risk [12–14]. Because each individual has different frequencies and combinations of these variants, they hold great promise to personalize both prostate cancer screening and treatment algorithms.
GERMLINE PROSTATE CANCER RISK VARIANTS AND SCREENING
Common genetic variations, called single nucleotide polymorphisms (SNPs), are thought to directly contribute to the development of many complex diseases including prostate cancer . As previously mentioned, many advances in genotyping have enabled genome-wide association studies (GWAS) to identify approximately 100 SNPs that are associated with prostate cancer susceptibility and are thought to explain more than 35% of the heritable component of prostate cancer [16▪]. Furthermore, as these germline SNPs are stable throughout a man's lifetime, and are not influenced by other disease processes (e.g. inflammation, infection, benign prostate growth), there is interest in their use as biomarkers to improve prostate cancer screening strategies .
Several studies have evaluated various combinations of the prostate cancer risk SNPs to assess their combined affects in defining prostate cancer susceptibility. For example, the first published study evaluated a panel of five prostate cancer risk SNPs. Carriers of all five risk SNPs who had a family history of prostate cancer had a nearly 9.5-fold increased risk for developing the disease compared with men without a family history carrying no risk alleles . Another study examined a set of 14 prostate cancer risk SNPs and calculated both relative and absolute risks of being diagnosed with prostate cancer . Considering men with 11 prostate cancer risk-associated alleles (average in general population) and negative family history as having baseline risk, men who had 14 or more risk alleles and a family history of prostate cancer had calculated odds ratios (ORs) of 4.92 and 3.88 for prostate cancer in a Swedish and US cohort, respectively. Furthermore, on the basis of these data, it was estimated that a 55-year-old man with a family history of prostate cancer who was also a carrier of all 14 prostate cancer risk-associated SNPs had more than 50% risk of being diagnosed with the disease over a 20-year period. In comparison, without applying the SNP genotype or family history, these same men would have been predicted to have an average population absolute risk of 13% .
As additional prostate cancer risk SNPs have been identified, studies have continued to evaluate their performance at predicting prostate cancer risk. For example, Kote-Jarai et al. evaluated 15 prostate cancer risk associated SNPs in a large consortium of 7370 prostate cancer cases and 5742 controls and found a strong cumulative effect on prostate cancer risk. Men in the top 10% of the risk distribution based on these 15 SNPs had a 2.1-fold increased risk relative to general population rates. Similarly, Lindstrom et al.  evaluated 25 prostate cancer risk SNPs in 7509 prostate cancer cases and 7652 controls and found that compared with men who were carriers of the lowest number of prostate cancer risk SNPs (i.e. the lowest tenth percentile), men who were carriers of the highest number of prostate cancer risk SNPs (i.e. in the top tenth percentile) had more than a five-fold risk of being diagnosed with prostate cancer. The authors also found that a model that incorporated SNPs had a better discriminative performance than family history, especially in men who were younger than 60 years old. Finally, other studies involving panels of 33 SNPs have documented similar utility and offer better discrimination between men with prostate cancer from those without than any other clinical variable [22,23▪,24,25].
It is apparent that panels of prostate cancer risk SNPs can risk stratify men who have increased disease susceptibility. On the basis of this, it is reasonable that targeted screening could be directed towards men who are carriers of relatively increased numbers of prostate cancer SNPs. As such, these SNPs could provide an answer to one of the biggest criticisms of PSA screening by selecting only those men who have an increased risk.
GENETIC VARIANTS AND PSA SCREENING
Common genetic variants also offer a potential opportunity to improve upon the interpretation of serum PSA values [26,27]. For example, it has previously been estimated that 40–45% of the inter-individual variability in measured serum PSA concentrations can be explained by genetic factors [28,29]. Recent studies have shown that SNPs in or near the gene that encodes PSA [e.g. kallikrein related peptidase 3 (KLK3)] can influence serum PSA concentrations and subsequently impact the frequency of prostate cancer screening and detection [26,27,30–38]. In addition, other studies have documented variants within the PSA gene that influence PSA expression in other racial cohorts of men [39,40].
The results of a recent GWAS documented that several prostate cancer risk SNPs show strong associations with serum PSA levels (called PSA-SNPs) . Furthermore, the authors demonstrated that four PSA-SNPs could be used to adjust a man's measured serum PSA . These genetically corrected PSA values significantly improved the performance of PSA as a screening tool [area under the curve (AUC) 73.2%] compared with uncorrected values (AUC 70.9%) [41,42]. Finally, it was shown in a cohort of men of European ancestry without documented prostate cancer that genetic correction for the presence of the four PSA-SNPs could potentially result in an 18–22% reduction in the number of potentially unnecessary biopsies (defined by those men whose measured serum PSA fell below a biopsy threshold after correction for the SNPs) . In addition, genetic correction for the absence of the PSA-SNPs could result in a 3% reduction in potentially delayed biopsies, defined by those men whose measured serum PSA went above a biopsy threshold after correction for the SNPs . When genetic correction was applied to a cohort of African-American men, the same PSA-SNPs yielded different results: genetic correction prevented no unnecessary biopsies, but could have been used to avoid delaying necessary biopsies in 30% of patients . The racial differences in genetic correction are intriguing, as it is known that African-American men are significantly more likely to develop more advanced stage disease and have twice the prostate cancer specific mortality than men of European ancestry [31,44–47]. Genetically corrected PSA levels in both European and African-Americans may allow physicians to more accurately gauge the risk of prostate cancer and thus avoid unnecessary and/or delays in diagnosis .
PSA-SNPs may also have additional clinical utilities. For example, recent studies have suggested that some of SNPs within or near PSA gene may be associated with prostate cancer aggressiveness [49–51,52▪]. Specifically, a retrospective analysis of a panel of 36 prostate cancer risk SNPs performed by the NCI SPORE Genetics Working Group  suggests SNP rs2735839 within the PSA gene on chromosome 19q13 (unpublished data). After adjusting for multiple testing, only prostate cancer risk SNP rs2735839 was inversely and significantly associated with aggressive (OR 0.77; 95% CI 0.69–0.87) and high-grade disease (OR 0.77; 95% CI 0.68–0.86) in European men. Similar associations were documented in African-American individuals. The ability of rs2735839 to discriminate among disease aggressiveness at different PSA levels, as measured by AUC, ranged from 0.77 to 0.82 in European men and from 0.66 to 0.75 in African-American men. Although the cause of these associations remains subject to debate, and the results need to be validated in other cohorts, it appears that some of the PSA-SNPs may have clinical utility in identifying men with high-grade disease.
On the basis of these results, it is possible that PSA-SNPs could be used to improve PSA screening. In doing so, it could help distinguish which men are likely to harbour prostate cancer and potentially aggressive disease. In addition, genetic correction of serum PSA values could also identify which men have elevated PSA values that are unrelated to prostate cancer. In doing so, the PSA-SNPs could potentially avoid unnecessary biopsies in genetically high PSA producers and a potential delay in biopsies for genetically low PSA producers. Finally, at least one of the PSA-SNPs may also have additional clinical utility in identifying men with aggressive disease.
GERMLINE PROSTATE CANCER RISK VARIANTS AND BIOPSY RESULTS
Currently, abnormal PSA values and digital rectal examinations determine the need for prostate biopsy. However, only about 30–40% of men with abnormal PSA values or physical examination findings are routinely diagnosed with prostate cancer on transrectal ultrasound guided biopsy . Recent studies have evaluated germline prostate cancer risk SNPs to predict prostate cancer diagnosis on biopsy in men of European ancestry [54,55] and different racial populations [56–58]. For example, Aly et al. evaluated a panel of 35 prostate cancer risk SNPs in over 5000 Swedish men who underwent a prostate biopsy. The authors found that using SNPs could help to reduce the number of potentially unnecessary biopsies. For example, if men who carried only a low number of prostate cancer risk SNPs did not undergo biopsy, then 22.7% of biopsies could be avoided. However, it should be acknowledged that this strategy would miss 3% of patients with aggressive disease. In another study, Kader et al.[23▪] compared the performance of 33 prostate cancer risk SNPs with existing clinical parameters in predicting positive prostate biopsies in the REDUCE trial. All men in the trial had an initial negative prostate biopsy and underwent study-mandated biopsies at 2 and 4 years . The overall risk of prostate cancer was estimated and ranked for each patient in the placebo arm of the REDUCE trial on the basis of the clinical model only and a combined model incorporating clinical characteristics and the PSA-risk SNPs [23▪]. The authors found that adding the prostate cancer risk SNPs to the best clinical model reclassified prostate cancer risk in 33% of men, and the reclassified risk had a significantly better correlation to biopsy outcomes. In addition, the AUC for discriminating prostate biopsy results increased from 0.62 using the clinical model only to 0.66 using the combined clinical and genetic model. A similar and overall general benefit of using prostate cancer risk SNPs to predict biopsy outcomes was also reported in other ethnic populations [56–58].
Both family history and the prostate cancer risk SNPs are measures of the genetic susceptibility to prostate cancer. Family history can be variable (e.g. influenced by family size, family communication and/or recall ability) and change over time (e.g. if a relative has not been screened or diagnosed until a future time point). As mentioned above, the number of prostate cancer risk SNPs are stable and can be determined based upon a simple blood test. Recent studies have used these prostate cancer risk SNPs to calculate a Genetic Risk Score (GRS). A GRS is calculated on the basis of the genotypes of multiple prostate cancer risk SNPs, weighted by their relative risk to prostate cancer. The GRS is weighted to the median of the general population. For example, when using a panel of 33 risk SNPs, approximately 50, 8 and 2% of men have a GRS that is one, two and three-fold higher than the average man in the US population [23▪]. In some studies, it has been shown that increasing GRS are associated with significantly higher rates of prostate cancer detection. For example, in a population of Chinese men, it was found that biopsy detection rates increase with increasing GRS; 26.3, 43.2 and 60.0% for men with low, average and higher GRS, respectively . For patients with moderately elevated PSA levels (<20 ng/ml), the prostate cancer detection rate was 31.2% overall and was 16.7, 31.2 and 40.9% for men with lower, average and higher GRS, respectively. For patients with PSA more than 20 ng/ml, however, the prostate cancer detection rates were high (∼70%) regardless of GRS.
Several studies have demonstrated that in comparison to knowledge of family history of prostate cancer, GRS is significantly better in discriminative ability [23▪,60▪]. Specifically, the AUC of GRS (0.58–0.62) for discriminating prostate cancer cases compared with controls was significantly higher than family history (0.51–0.55).
Taken together, the results suggest the prostate cancer risk SNPs can be used to calculate a GRS that can be used to improve prostate cancer prediction on biopsy. It should be noted that there are currently several newer commercially available tests, such as PCA3 [61,62] and prostate health index (PHI) , which offer improved prostate cancer risk prediction compared with PSA. However, it is unknown how the prostate cancer SNP's performance compares or potentiates these tests. Further research into these relationships should be explored. However, if incorporated into routine clinical practice, the prostate cancer risk SNPs offer the possibility to improve screening practices by targeting those men who carry the highest number and thereby help reduce the number of potentially unnecessary biopsies performed.
The past decade has witnessed major advancements in genetic sequencing technologies that have directly and proportionately increased our understanding of the genetic basis of prostate cancer. Specifically, there are now almost 100 different germline SNPs that have reproducibly been associated with prostate cancer susceptibility and possibly aggressiveness. Incorporation of these tests into clinical practice offers potential to provide improvements in patient selection for prostate cancer screening; PSA interpretation (e.g. using genetic correction using PSA SNPs); decision for biopsy (using prostate cancer risk SNPs); and possibly the decision for treatment. A proposed clinical algorithm incorporating these prostate cancer risk SNPs is demonstrated (Fig. 1).
Finally, it is important to note that although excellent progress has been made in delineating the genetic basis of prostate cancer, more genetic studies are needed to better understand the genetic susceptibility to prostate cancer, especially aggressive tumours. Such genetic markers would be extremely important to address the current debate on PSA screening, overdiagnosis and overtreatment of prostate cancer. Identification and refinement of these genetic variants will permit additional tools that can be incorporated into algorithms that can improve current clinical practices.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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