Validation of Association of Genetic Variants at 10q with PSA Levels in Men at High Risk for Prostate Cancer

摘要

Objectives class="unordered" style="list-style-type:disc" id="L1">Men with a family history of prostate cancer and African American men are at increased risk for prostate cancer and stand to benefit from individualized interpretation of PSA to guide screening strategies.The purpose of this study was to validate six previously identified markers among high-risk men enrolled in the Prostate Cancer Risk Assessment Program - a prostate cancer screening study.Patients and Methods class="unordered" style="list-style-type:disc" id="L2">Eligibility for PRAP includes men ages 35–69 years with a family history of prostate cancer, any African American male regardless of family history, and men with known BRCA gene mutations.GWAS markers assessed included rs2736098 (5p15.33), rs10993994 (10q11), rs10788160 (10q26), rs11067228 (12q24), rs4430796 (17q12), and rs17632542 (19q13.33).Genotyping methods included either Taqman® SNP Genotyping Assay (Applied Biosystems) or pyrosequencing.Linear regression models were used to evaluate the association between individual markers and log-transformed baseline PSA levels, while adjusting for potential confounders.Results class="unordered" style="list-style-type:disc" id="L3">707 participants (37% Caucasian, 63% African American) with clinical and genotype data were included in the analysis.Rs10788160 (10q26) strongly associated with PSA levels among high-risk Caucasian participants (p<0.01), with a 33.2% increase in PSA level with each A-allele carried.Furthermore, rs10993994 (10q11) demonstrated an association to PSA level (p=0.03) in high-risk Caucasian men, with a 15% increase in PSA with each T-allele carried.A PSA adjustment model based on allele carrier status at rs10788160 and rs10993994 is proposed specific to high-risk Caucasian men.Conclusion class="unordered" style="list-style-type:disc" id="L4">Genetic variation at 10q may be particularly important in personalizing interpretation of PSA for high-risk Caucasian men.Such information may have clinical relevance in shared decision-making and individualized prostate cancer screening strategies for high-risk Caucasian men. Further study is warranted. class="kwd-title">Keywords: genetics, prostate-specific antigen, screening, prostatic neoplasms, family history class="head no_bottom_margin" id="S5title">IntroductionProstate cancer is the second-leading cause of cancer-related deaths in men in the United States (). Men with a family history of prostate cancer and African American men are considered to be at high-risk for prostate cancer (–), with subsets at increased risk for younger age at diagnosis and aggressive disease (–). Given these factors, high-risk men in particular stand to benefit from optimized prostate cancer screening approaches.PSA-based methods for prostate cancer screening remain controversial for the general population due to lack of consistency in reducing mortality and the estimated number needed to screen to prevent a prostate cancer death (–). There is concern for early detection leading to significant overdiagnosis and overtreatment of indolent prostate cancer, and standard therapy commonly results in significant morbidity and well-documented negative impacts on urinary, bowel and sexual function (). Furthermore, PSA may show “false-positive” elevations, thus leading to unnecessary testing and prostate biopsies, which have the potential for serious complications (). Yet, prostate cancer detection has been reported even at lower PSA values <3.0 (, , ). Based on these studies, several national organizations have offered sharply different 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 having symptoms of prostate cancer, stating that the harms resulting from screening outweigh 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 high-risk men have this discussion at age 45 (). The American Urologic Association supports the appropriate use of the PSA test for screening () and recommends men speak with their doctors about their risk for prostate cancer. In addition, the American Society of Clinical Oncology (ASCO) 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 (). ASCO also stressed the importance of shared decision-making between patients and providers. Thus there is a need to develop approaches to optimize risk assessment for prostate cancer particularly for high-risk men, and one approach is to individualize interpretation of PSA in order to make appropriately informed prostate cancer screening recommendations.Genetic variation has been reported to associate with PSA levels, with potential implications for adjustment of PSA based on genotype. A prior genomewide association study for prostate cancer reported the association of multiple genetic variants, particularly on chromosomes 10 and 19, with PSA levels (href="#R22" rid="R22" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489718">22). 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 upon PSA for prostate cancer risk stratification (href="#R23" rid="R23" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_517874677">23). In 2010, Gudmundsson et al reported findings from a PSA-focused genomewide association study and identified six genetic variants associated with PSA in primarily average-risk Caucasian men (href="#R24" rid="R24" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489698">24). An additional goal of this previous study was to develop individualized PSA-cutoffs 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 marginal benefit to adding 33 prostate cancer-associated SNPs to PSA (href="#R25" rid="R25" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489711">25), while another study reported that four genetic variants can be useful in correcting PSA, leading to a reduction in unnecessary prostate biopsies (href="#R26" rid="R26" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489708">26). These prior 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 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.Our study was performed to validate the findings of the association of six genetic variants previously found to be associated with PSA levels (href="#R24" rid="R24" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489692">24) in a high-risk, ethnically diverse cohort of men undergoing prostate cancer screening in the Prostate Cancer Risk Assessment Program (PRAP) (href="#R7" rid="R7" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489690">7). Since high-risk men are at increased risk for a diagnosis of prostate cancer (particularly at younger ages)(href="#R6" rid="R6" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489703">6, href="#R7" rid="R7" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_370489705">7), PRAP is an ideal, diverse cohort in which to study candidate genetic variants for association to PSA levels and to develop adjustments to PSA based on genetic information particularly relevant to high-risk men.