Abstract
Background: Several prostate cancer genome-wide association studies (GWAS) have identified risk-associated genetic variants primarily in populations of European descent. Less is known about the association of these variants in high-risk populations, including men of African descent and men with a family history of prostate cancer. This article provides a detailed review of published studies of prostate cancer–associated genetic variants originally identified in GWAS and replicated in high-risk populations.
Methods: Articles replicating GWAS findings (National Human Genome Research Institute GWAS database) were identified by searching PubMed and relevant data were extracted.
Results: Eleven replication studies were eligible for inclusion in this review. Of more than 30 single-nucleotide polymorphisms (SNP) identified in prostate cancer GWAS, 19 SNPs (63%) were replicated in men of African descent and 10 SNPs (33%) were replicated in men with familial and/or hereditary prostate cancer (FPC/HPC). The majority of SNPs were located at the 8q24 region with modest effect sizes (OR 1.11–2.63 in African American men and OR 1.3–2.51 in men with FPC). All replicated SNPs at 8q24 among men of African descent were within or near regions 2 and 3.
Conclusions: This systematic review revealed several GWAS markers with replicated associations with prostate cancer in men of African descent and men with FPC/HPC. The 8q24 region continues to be the most implicated in prostate cancer risk. These replication data support ongoing study of clinical utility and potential function of these prostate cancer–associated variants in high-risk men.
Impact: The replicated SNPs presented in this review hold promise for personalizing risk assessment for prostate cancer for high-risk men upon further study. Cancer Epidemiol Biomarkers Prev; 20(8); 1599–610. ©2011 AACR.
Introduction
Prostate cancer is the most commonly diagnosed noncutaneous cancer among men in the United States (1). For 2011, the American Cancer Society projects that approximately 240,890 new cases of prostate cancer will be diagnosed and that about 33,720 men will die from prostate cancer (1). African American men and men with a family history of prostate cancer are at significantly increased risk for developing prostate cancer, with some developing aggressive disease or having younger age of onset (2). African American men are at twice the risk for developing prostate cancer and are at more than twice the risk for dying from prostate cancer (3). Men with familial prostate cancer (FPC), defined as having at least 1 first-degree relative with prostate cancer, or hereditary prostate cancer (HPC), defined as a family with 3 generations affected, 3 first-degree relatives affected, or 2 relatives affected before age 55 years, are at 2 to 7 times increased risk for developing prostate cancer (4, 5).
Many genetic linkage and association studies have attempted to identify high-penetrance genetic variants that confer increased risk of developing prostate cancer and particularly of prostate cancer in high-risk populations, which includes African American men and men with FPC/HPC. However, causal genetic variants underlying susceptibility remain unknown due to the genetic complexity of prostate cancer. The increase in high-throughput technology and decreases in cost have made genome-wide association studies (GWAS) easier to conduct and have lead to the ability to identify associations between disease and more common variants in the genome. To date, many prostate cancer GWAS have been conducted; however, these studies have primarily been in populations of European descent and have been powered by mostly sporadic prostate cancer cases (6). Furthermore, most identified variants have shown very low penetrance and few have shown biological plausibility.
Replication studies have become increasingly important to validate associations in diverse race/ethnic populations and disease subtypes and to place variants identified in the context of their potential clinical utility in predicting individual disease risk. Although the genetic variants detected in GWAS have been of modest effect sizes (e.g., ORs of 1.01–1.5), understanding the risk particularly in men of African descent men and men with FPC/HPC may have clinical prediction utility in high-risk men (7). One area in need of accurate prostate cancer risk prediction is prostate cancer screening, particularly for high-risk men. Prostate cancer screening guidelines remain an issue of debate among the general population, and optimized approaches to screening high-risk men remain understudied. Therefore, identifying genetic variants associated with or predicting prostate cancer risk in high-risk men is increasingly important to develop individualized screening and prevention strategies based on genetic risk.
Here, we present a systematic review of published replication studies of single-nucleotide polymorphisms (SNP) associated with prostate cancer initially identified in GWAS and replicated in men of African descent men and men with FPC/HPC. The goal of this review was to determine the rates of positive associations with prostate cancer of GWAS SNPs in high-risk men and provide a consolidated source of SNPs to date associated with prostate cancer in high-risk men for further validation and study of clinical utility.
Methods
The national GWAS database maintained by the National Human Genome Research Institute of the NIH was searched for the term “prostate cancer” to identify prostate cancer risk associated SNPs from published GWAS as of February 2011 (6). In addition, PubMed was searched using the search terms: “prostate cancer” and “GWAS” or “genome-wide association study” or “genome-wide.” There were no limitations placed on population studied, publication year, or country. Relevant articles cited in the bibliography of retrieved articles were also included. Selection of articles was done by 2 independent researchers (M.B. Ishak and V.N. Giri) to avoid bias. SNP trait associations listed here include those with P values of less than 1.0 × 10−5 in the original GWAS, with at least 1 replication study in high-risk men. We opted to include 3 SNPs originally identified in GWAS in which the level of significance in the original GWAS was greater than 1.0 × 10−5 but had at least 2 replication studies reported in high-risk men. More than 30 unique genetic variants were found to be associated with prostate cancer through GWAS. We present data on the earliest published GWAS detecting an association with an SNP if more than 1 GWAS detected an association. In addition, we included a SNP identified in a GWAS conducted in an African American population (8).
A second search was conducted to identify replication studies evaluating those genetic variants initially identified in GWAS and further studied in men of African descent men and in men with FPC/HPC. There were no limitations placed on publication year or language. PubMed was searched using the search terms “prostate cancer” or “prostatic neoplasms” in combination with “African American” and “African descent” in combination with “genetic” and “gene” and “SNP” or “single nucleotide polymorphism” or in combination with “replication.” For replication studies in FPC/HPC, PubMed was searched using the search terms “prostate cancer” or “prostatic neoplasms” in combination with “familial prostate cancer” or “FPC” and “hereditary prostate cancer” or “HPC” in combination with “genetic” and “gene” and “SNP” or “single nucleotide polymorphism” or in combination with “replication.” We excluded data on SNPs that were not previously identified in GWAS and considered only SNPs that reached a P value of 0.05 in the specific high-risk populations due to a greater potential clinical impact of these genetic markers in risk assessment for high-risk men.
Extracted data from both GWAS and replication studies include study name, authors, population(s) studied, publication date (month and year), chromosomal region, potentially implicated gene(s), SNP reaching a statistical significance of α = 0.05 or lower, risk allele, sample size (number of case patients and number of control subjects in the first and subsequent stages), frequency of the risk allele, respective effect size and 95% CI, and P value. When available, we present the risk allele-specific OR. Otherwise, we presented the OR for particular genotypes.
The forest plots in this article were obtained using SAS 9.1.3 software and provide the OR and 95% CI for each replication study. Linkage disequilibrium (LD) visualizations were constructed in Haploview 4.2 (9).
Results
Ten GWAS were found to be eligible for inclusion in our study (6). Eleven replication studies conducted in men of African descent and 4 replication studies in men with FPC/HPC were eligible for inclusion in our review. Table 1 shows the replication studies in men of African descent. Of approximately 30 prostate cancer susceptibility variants identified from GWAS, 19 SNPs (63%) were found to be statistically significantly associated with prostate cancer in men of African descent, 9 of these SNPs (14% of prostate cancer–associated SNPs from GWAS) mapping to the 8q24 chromosomal region. The replication studies that have shown statistically significant associations between several SNPs on 8q24 and prostate cancer risk in men of African descent include rs16901979, rs10086908, rs13254738, rs6983561, rs7000448, rs6983267, rs1447295, rs10090154, and rs7017300. In addition, replication studies in men of African descent have found associations with rs2660753 on 3p12, rs10486567 on 7p15.2, rs10993994 on 10q11.2 near MSMB, rs7931342 and rs10896449 on 11q13, rs4430796 on 17q12, rs1859962 on 17q24.3, rs2735839 on 19q13.33 between the KLK2 and KLK3 genes, and rs5945572 and rs5945619 on Xp11.22. All 8q24 SNPs were replicated at statistical significance in more than 1 study, with the exceptions of rs10090154 and rs7017300.
Summary of prostate cancer–associated SNPs discovered in GWAS and replicated in men of African descent
| Gene | rs number | Positiona | Implicated in GWAS | Replication Study design | Disease phenotype | Risk allele | Association test OR (95% CI) | P | Reference | Correction for ancestry |
|---|---|---|---|---|---|---|---|---|---|---|
| 3p12 | rs2660753 | 87,193,364 | Eeles et al., 2008 (10) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.17 (1.02–1.35) | 0.029 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population |
| 7p15.2 (JAZF1) | rs10486567 | 27,943,088 | Thomas et al., 2008 (12) | Nested case–control (860 cases and 575 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.18 (1.00–1.40) | – | Waters et al., 2009 (13) | Models adjusted for age and proportion of European ancestry |
| Multicenter sample (2,899 cases and 2,538 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.18 (1.08–1.29) | 0.0002 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| 8q24 | rs16901979 | 128,194,098 | Gudmundsson et al., 2007 (15) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.38 (1.19–1.60) | 1.7E-05 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population |
| Multicenter sample (2,642 cases and 2,584 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.39 (1.28–1.52) | 1.9 E-14 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Hospital-based case–control (490 cases and 567 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.5 (1.1–2.2) | 0.008 | Robbins et al., 2007 (16) | Model adjusted for age and global and local 8q24 ancestry | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.60 (1.17–2.19) | 0.003 | Wang et al., 2010 (17) | Noneb | ||||
| Case–control (338 cases and 426 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.41 (1.02–1.95) | 0.03 | Okobia et al, 2011 (18) | None | ||||
| Case–control (156 cases and 231 controls) | Early onset prostate cancer (diagnosed among 65 years and younger) | A | OR (A allele) = 2.30 (1.40–3.77) | 0.001 | Okobia et al., 2011 (18) | None | ||||
| rs10086908 | 128,081,119 | Al Olama et al., 2009 (19) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.31 (1.11–1.55) | 1.1E-03 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (861 cases and 876 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.31 (1.11–1.54) | 0.001 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| rs13254738 | 128,173,525 | Ghoussaini et al., 2008 (20) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.36 (1.17–1.58) | 4.9E-05 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (2,557 cases and 2,277 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.29 (1.18–1.41) | 1.03 × 10−8 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Nested case–control (1,614 cases and 837 controls | Sporadic prostate cancer | C | OR (C allele) = 1.24 (1.09–1.42) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs6983561 | 128,176,062 | Al Olama et al., 2009 (19) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.31 (1.13–1.52) | 2.8E-04 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (2,764 cases and 3,255 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.37 (1.27–1.49) | 3.5 E-15 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.55 (1.15–2.09) | 0.0039 | Wang et al., 2010 (17) | Noneb | ||||
| Nested case–control (1,614 cases and 837 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.34 (1.18–1.53) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs7000448 | 128,510,352 | Ghoussaini et al., 2008 (20) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.20 (1.03–1.40) | 0.016 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (1,698 cases and 2,329 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.27 (1.15–1.41) | 3.0 E-6 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.41 (1.03–1.94) | 0.03 | Wang et al., 2010 (17) | Noneb | ||||
| Nested case–control (1,614 cases and 837 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.33 (1.12–1.58) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs6983267 | 128,482,487 | Yeager et al., 2007 (22); Thomas et al., 2008 (12) | Multicenter sample (3,666 cases and 2,992 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.32 (1.18–1.49) | 3.3 E-6 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | T | OR (T allele) = 0.6 (0.4–0.7) | 1.3 E-4 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry | ||||
| Nested case–control (1,614 cases and 837 controls | Sporadic prostate cancer | G | 1.43 (1.17–1.75) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs1447295 | 128,554,220 | Amundadottir et al., 2006 (24) | Multicenter sample (3,167 cases and 3,325 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.11 (1.02–1.21) | 0.014 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Case–control (171 cases and 256 cases) | Sporadic prostate cancer; diagnosed among men of 65 years and younger | A | OR AA genotype = 2.63 (1.14–6.05) | Schumacher et al., 2007 (25) | None | |||||
| rs10090154 | 128,601,319 | Al Olama et al., 2009 (19) | Multicenter sample (1,683 cases and 1,403 controls) | Sporadic prostate cancer | T | 1.20 (1.04–1.37) | 0.011 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| rs7017300 | 128,594,450 | Eeles et al., 2008 (10) | Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | C | OR (C allele) = 1.2 (1.0–1.5) | 0.03 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry | |
| 10q11.2 MSMB | rs10993994 | 51,219,502 | Eeles et al., 2008 (10) | Multicenter sample (3,374 cases and 2,982 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.12 (1.03–1.21) | 0.005 | Chang et al., 2011 (14) | Model adjusted for age and study center |
| 11q13 | rs7931342 | 68,751,073 | Eeles et al., 2008 (10) | Multicenter sample (2,445 cases and 2,018 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.15 (1.03–1.29) | 0.014 | Chang et al., 2011 (14) | Model adjusted for age and study center |
| rs10896449 | 68,751,243 | Thomas et al., 2008 (12) | Multicenter sample (2,056 cases and 1,898 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.12 (1.01–1.24) | 0.031 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 0.7 (0.54–0.93) | 0.009 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| 17q12 (HNF1B) | rs4430796 | 33,172,153 | Gudmundsson et al., 2007 (27) | Hospital-based case–control study (364 cases and 353 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.26 (1.01–1.56) | 0.04 | Sun et al., 2008 (28) | Nonec |
| Multicenter sample (3,112 cases and 2,911 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.08 (1.00–1.18) | 0.053 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.48 (1.11–1.96) | 0.008 | Hooker et al., 2010 (26) | IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.16 (1.00-1.34) | 0.056 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | ||||
| 17q21 (ZNF652) | rs7210100 | 44,791,748 | Haiman et al., 2011 (8) | Original GWAS in AA men | OR (per allele) = 1.51 | 3.4 × 10−13 | – | Adjusted for age and ancestry | ||
| 17q24.3 | rs1859962 | 66,620,348 | Eeles et al., 2008 (10) | Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | G | OR (G Allele) = 1.2 (1.0–1.5) | 0.033 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry |
| 19q13.33 (KLK2 and KLK3) | rs2735839 | 56,056,435 | Eeles et al., 2008 (10) | Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 0.78 (0.60–1.00) | 0.04 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease |
| Xp11.22 (NUDT10/11) | rs5945572 | 51,246,423 | Gudmundsson et al., 2008 (29) | Nested case–control (860 cases and 575 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.34 (1.05–1.71) | – | Waters et al., 2009 (13) | Models adjusted for age and proportion of European ancestry |
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | 1.48 (1.01–2.16) | 0.05 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| Multicenter sample (1,764 cases and 1,235 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.11 (1.02–1.20) | 0.02 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| rs5945619 | 51,258,412 | Eeles et al., 2008 (10) | Multicenter sample (1,390 cases and 1,845 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.09 (1.00–1.18) | 0.039 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Gene | rs number | Positiona | Implicated in GWAS | Replication Study design | Disease phenotype | Risk allele | Association test OR (95% CI) | P | Reference | Correction for ancestry |
|---|---|---|---|---|---|---|---|---|---|---|
| 3p12 | rs2660753 | 87,193,364 | Eeles et al., 2008 (10) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.17 (1.02–1.35) | 0.029 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population |
| 7p15.2 (JAZF1) | rs10486567 | 27,943,088 | Thomas et al., 2008 (12) | Nested case–control (860 cases and 575 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.18 (1.00–1.40) | – | Waters et al., 2009 (13) | Models adjusted for age and proportion of European ancestry |
| Multicenter sample (2,899 cases and 2,538 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.18 (1.08–1.29) | 0.0002 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| 8q24 | rs16901979 | 128,194,098 | Gudmundsson et al., 2007 (15) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.38 (1.19–1.60) | 1.7E-05 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population |
| Multicenter sample (2,642 cases and 2,584 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.39 (1.28–1.52) | 1.9 E-14 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Hospital-based case–control (490 cases and 567 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.5 (1.1–2.2) | 0.008 | Robbins et al., 2007 (16) | Model adjusted for age and global and local 8q24 ancestry | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.60 (1.17–2.19) | 0.003 | Wang et al., 2010 (17) | Noneb | ||||
| Case–control (338 cases and 426 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.41 (1.02–1.95) | 0.03 | Okobia et al, 2011 (18) | None | ||||
| Case–control (156 cases and 231 controls) | Early onset prostate cancer (diagnosed among 65 years and younger) | A | OR (A allele) = 2.30 (1.40–3.77) | 0.001 | Okobia et al., 2011 (18) | None | ||||
| rs10086908 | 128,081,119 | Al Olama et al., 2009 (19) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.31 (1.11–1.55) | 1.1E-03 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (861 cases and 876 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.31 (1.11–1.54) | 0.001 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| rs13254738 | 128,173,525 | Ghoussaini et al., 2008 (20) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.36 (1.17–1.58) | 4.9E-05 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (2,557 cases and 2,277 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.29 (1.18–1.41) | 1.03 × 10−8 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Nested case–control (1,614 cases and 837 controls | Sporadic prostate cancer | C | OR (C allele) = 1.24 (1.09–1.42) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs6983561 | 128,176,062 | Al Olama et al., 2009 (19) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.31 (1.13–1.52) | 2.8E-04 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (2,764 cases and 3,255 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.37 (1.27–1.49) | 3.5 E-15 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.55 (1.15–2.09) | 0.0039 | Wang et al., 2010 (17) | Noneb | ||||
| Nested case–control (1,614 cases and 837 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.34 (1.18–1.53) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs7000448 | 128,510,352 | Ghoussaini et al., 2008 (20) | Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.20 (1.03–1.40) | 0.016 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | |
| Multicenter sample (1,698 cases and 2,329 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.27 (1.15–1.41) | 3.0 E-6 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Community-based case–control (127 cases and 345 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.41 (1.03–1.94) | 0.03 | Wang et al., 2010 (17) | Noneb | ||||
| Nested case–control (1,614 cases and 837 controls) | Sporadic prostate cancer | C | OR (C allele) = 1.33 (1.12–1.58) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs6983267 | 128,482,487 | Yeager et al., 2007 (22); Thomas et al., 2008 (12) | Multicenter sample (3,666 cases and 2,992 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.32 (1.18–1.49) | 3.3 E-6 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | T | OR (T allele) = 0.6 (0.4–0.7) | 1.3 E-4 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry | ||||
| Nested case–control (1,614 cases and 837 controls | Sporadic prostate cancer | G | 1.43 (1.17–1.75) | – | Haiman et al., 2007 (21) | Model adjusted for genome-wide European ancestry and study | ||||
| rs1447295 | 128,554,220 | Amundadottir et al., 2006 (24) | Multicenter sample (3,167 cases and 3,325 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.11 (1.02–1.21) | 0.014 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Case–control (171 cases and 256 cases) | Sporadic prostate cancer; diagnosed among men of 65 years and younger | A | OR AA genotype = 2.63 (1.14–6.05) | Schumacher et al., 2007 (25) | None | |||||
| rs10090154 | 128,601,319 | Al Olama et al., 2009 (19) | Multicenter sample (1,683 cases and 1,403 controls) | Sporadic prostate cancer | T | 1.20 (1.04–1.37) | 0.011 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| rs7017300 | 128,594,450 | Eeles et al., 2008 (10) | Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | C | OR (C allele) = 1.2 (1.0–1.5) | 0.03 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry | |
| 10q11.2 MSMB | rs10993994 | 51,219,502 | Eeles et al., 2008 (10) | Multicenter sample (3,374 cases and 2,982 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.12 (1.03–1.21) | 0.005 | Chang et al., 2011 (14) | Model adjusted for age and study center |
| 11q13 | rs7931342 | 68,751,073 | Eeles et al., 2008 (10) | Multicenter sample (2,445 cases and 2,018 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.15 (1.03–1.29) | 0.014 | Chang et al., 2011 (14) | Model adjusted for age and study center |
| rs10896449 | 68,751,243 | Thomas et al., 2008 (12) | Multicenter sample (2,056 cases and 1,898 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.12 (1.01–1.24) | 0.031 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 0.7 (0.54–0.93) | 0.009 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| 17q12 (HNF1B) | rs4430796 | 33,172,153 | Gudmundsson et al., 2007 (27) | Hospital-based case–control study (364 cases and 353 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.26 (1.01–1.56) | 0.04 | Sun et al., 2008 (28) | Nonec |
| Multicenter sample (3,112 cases and 2,911 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.08 (1.00–1.18) | 0.053 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.48 (1.11–1.96) | 0.008 | Hooker et al., 2010 (26) | IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| Case–control (868 cases and 878 controls) | Sporadic prostate cancer | T | OR (T allele) = 1.16 (1.00-1.34) | 0.056 | Xu et al., 2009 (11) | Model adjusted for age, ancestry proportion, and study population | ||||
| 17q21 (ZNF652) | rs7210100 | 44,791,748 | Haiman et al., 2011 (8) | Original GWAS in AA men | OR (per allele) = 1.51 | 3.4 × 10−13 | – | Adjusted for age and ancestry | ||
| 17q24.3 | rs1859962 | 66,620,348 | Eeles et al., 2008 (10) | Population-based case study (417 cases and 925 Illumina controls) | Sporadic prostate cancer | G | OR (G Allele) = 1.2 (1.0–1.5) | 0.033 | Xu et al., 2010 (23) | Model adjusted for proportion of West African ancestry |
| 19q13.33 (KLK2 and KLK3) | rs2735839 | 56,056,435 | Eeles et al., 2008 (10) | Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | OR (A allele) = 0.78 (0.60–1.00) | 0.04 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease |
| Xp11.22 (NUDT10/11) | rs5945572 | 51,246,423 | Gudmundsson et al., 2008 (29) | Nested case–control (860 cases and 575 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.34 (1.05–1.71) | – | Waters et al., 2009 (13) | Models adjusted for age and proportion of European ancestry |
| Hospital-based case–control (454 cases and 301 controls) | Sporadic prostate cancer | A | 1.48 (1.01–2.16) | 0.05 | Hooker et al., 2010 (26) | Model adjusted for IA estimates from 100 AIMs; same SNP not associated with aggressive disease | ||||
| Multicenter sample (1,764 cases and 1,235 controls) | Sporadic prostate cancer | A | OR (A allele) = 1.11 (1.02–1.20) | 0.02 | Chang et al., 2011 (14) | Model adjusted for age and study center | ||||
| rs5945619 | 51,258,412 | Eeles et al., 2008 (10) | Multicenter sample (1,390 cases and 1,845 controls) | Sporadic prostate cancer | G | OR (G allele) = 1.09 (1.00–1.18) | 0.039 | Chang et al., 2011 (14) | Model adjusted for age and study center | |
Abbreviations: AA, African American; IA, individual ancestry; AIM, ancestry informative markers.
aPosition based on NCBI Build 36.
bStudy reports similar results found when adjusted for age and proportion of African ancestry.
cStudy reports similar results found when models adjusted for proportion of African ancestry.
Figure 1 presents regions 1 to 3 of the 8q24 locus and the LD patterns. The map was based on D-prime using genotype data from the HapMap ASW population of African Americans in the southwest United States. The positions of the replicated SNPs in the 8q24 region are noted in Figure 1. As can be seen, all 9 of the replicated SNPs in men of African descent fall within or near region 2 and region 3 on 8q24.
Map of LD structure in the HapMap population of African Americans in the southwest United States (ASW) of chromosome 8q24 region 1 (126.54–128.62 Mb), region 2 (128.14–128.28 Mb), and region 3 (128.47–128.54 Mb).
Map of LD structure in the HapMap population of African Americans in the southwest United States (ASW) of chromosome 8q24 region 1 (126.54–128.62 Mb), region 2 (128.14–128.28 Mb), and region 3 (128.47–128.54 Mb).
Four replication studies conducted in FPC/HPC cases were eligible for inclusion in our review (Table 2). A total of 10 SNPs (33% of prostate cancer–associated SNPs from GWAS) were associated with prostate cancer in men with FPC/HPC. Replicated SNPs on 8q24 include rs1447295, rs4242382, rs6983561, rs6983267, rs7017300, rs7837688, rs10090154, and rs16901979. Furthermore, rs5945572 and rs5945619 on Xp.11 have also been replicated in FPC/HPC. Figure 2 presents a forest plot comparison of the effect sizes as measured by ORs of SNPs at 8q24 replicated among FPC/HPC cases. For SNPs replicated in both men of African descent and FPC/HPC cases, the effect sizes are larger among FPC/HPC studies, particularly for rs6983561, rs7017300, and rs10090154.
SNPs replicated in FPC/HPC
| Gene | rs number | Positiona | Implicated in GWAS | Replication Study design | Disease phenotype | Risk allele | Association test OR (95% CI) | P | Reference | Model description |
|---|---|---|---|---|---|---|---|---|---|---|
| Xp11 | rs5945572 | 51,246,423 | Gudmundsson et al., 2008 (29); Eeles et al., 2008 (10) | 168 HPC families | HPC (≥2 first-degree affected family members) | A | – | 0.009 | Lu et al., 2009 (30) | P value reported for overtransmission from parents to affected offspring |
| rs5945619 | 51,258,412 | Eeles et al., 2008 (10) | 168 HPC families | HPC (≥2 first-degree affected family members) | C | – | 0.03 | Lu et al., 2009 (30) | P value reported for overtransmission from parents to affected offspring | |
| 8q24 | rs1447295 | 128,554,220 | Amundadottir et al., 2006 (24) | Case–control (435 FPC cases and 545 population-based controls) | FPC (families have ≥3 affected family members) | A | OR (A allele) = 1.93 (1.37–2.72) | 0.0004 | Wang L. et al., 2007 (31) | None, similar results when adjusted for age |
| Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 2.25 (1.52–3.32) | 4.8 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | ||||
| rs4242382 | 128,586,755 | Thomas et al., 2008 (12) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 2.37 (1.61–3.50) | 1.39 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs6983561 | 128,176,062 | Al Olama et al., 2009 (19) | Case–control (542 affected men and 473 of their unaffected brothers) | FPC (men diagnosed with prostate cancer with ≥1 first- or second-degree living affected family member | C | OR (C allele) = 2.26 (1.06–4.83) | 0.03 | Beebe-Dimmer J.L. et al., 2008 (33) | None | |
| Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | C | ORhom/het = 1.76 (1.05–2.94) | 0.03 | Sun J. et al., 2008 (32) | Model adjusted for age | ||||
| rs6983267 | 128,482,487 | Yeager et al., 2007 (22); Thomas et al., 2008 (12) | Case–control (542 affected men and 473 of their unaffected brothers) | FPC (men diagnosed with prostate cancer with ≥1 first- or second-degree living affected family member | G | OR (G allele) = 1.30 (0.99–1.71) | 0.04 | Beebe-Dimmer J.L. et al., 2008 (33) | None | |
| rs7017300 | 128,594,450 | Eeles et al., 2008 (10) | Hospital-based case–control study 221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | C | ORhom/het = 1.86 (1.29–2.67) | 8.0 × 10−4 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs7837688 | 128,608,542 | Takata et al., 2010 (34) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | T | ORhom/het = 2.51 (1.71–3.70) | 3.2 × 10−6 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs10090154 | 128,601,319 | Al Olama et al., 2009 (19) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | T | ORhom/het = 2.33 (1.57–3.45) | 2.4 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs16901979 | 128,194,098 | Gudmundsson et al., 2007 (15) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 1.70 (1.02–2.84) | 0.04 | Sun J. et al., 2008 (32) | Model adjusted for age |
| Gene | rs number | Positiona | Implicated in GWAS | Replication Study design | Disease phenotype | Risk allele | Association test OR (95% CI) | P | Reference | Model description |
|---|---|---|---|---|---|---|---|---|---|---|
| Xp11 | rs5945572 | 51,246,423 | Gudmundsson et al., 2008 (29); Eeles et al., 2008 (10) | 168 HPC families | HPC (≥2 first-degree affected family members) | A | – | 0.009 | Lu et al., 2009 (30) | P value reported for overtransmission from parents to affected offspring |
| rs5945619 | 51,258,412 | Eeles et al., 2008 (10) | 168 HPC families | HPC (≥2 first-degree affected family members) | C | – | 0.03 | Lu et al., 2009 (30) | P value reported for overtransmission from parents to affected offspring | |
| 8q24 | rs1447295 | 128,554,220 | Amundadottir et al., 2006 (24) | Case–control (435 FPC cases and 545 population-based controls) | FPC (families have ≥3 affected family members) | A | OR (A allele) = 1.93 (1.37–2.72) | 0.0004 | Wang L. et al., 2007 (31) | None, similar results when adjusted for age |
| Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 2.25 (1.52–3.32) | 4.8 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | ||||
| rs4242382 | 128,586,755 | Thomas et al., 2008 (12) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 2.37 (1.61–3.50) | 1.39 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs6983561 | 128,176,062 | Al Olama et al., 2009 (19) | Case–control (542 affected men and 473 of their unaffected brothers) | FPC (men diagnosed with prostate cancer with ≥1 first- or second-degree living affected family member | C | OR (C allele) = 2.26 (1.06–4.83) | 0.03 | Beebe-Dimmer J.L. et al., 2008 (33) | None | |
| Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | C | ORhom/het = 1.76 (1.05–2.94) | 0.03 | Sun J. et al., 2008 (32) | Model adjusted for age | ||||
| rs6983267 | 128,482,487 | Yeager et al., 2007 (22); Thomas et al., 2008 (12) | Case–control (542 affected men and 473 of their unaffected brothers) | FPC (men diagnosed with prostate cancer with ≥1 first- or second-degree living affected family member | G | OR (G allele) = 1.30 (0.99–1.71) | 0.04 | Beebe-Dimmer J.L. et al., 2008 (33) | None | |
| rs7017300 | 128,594,450 | Eeles et al., 2008 (10) | Hospital-based case–control study 221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | C | ORhom/het = 1.86 (1.29–2.67) | 8.0 × 10−4 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs7837688 | 128,608,542 | Takata et al., 2010 (34) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | T | ORhom/het = 2.51 (1.71–3.70) | 3.2 × 10−6 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs10090154 | 128,601,319 | Al Olama et al., 2009 (19) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | T | ORhom/het = 2.33 (1.57–3.45) | 2.4 × 10−5 | Sun J. et al., 2008 (32) | Model adjusted for age | |
| rs16901979 | 128,194,098 | Gudmundsson et al., 2007 (15) | Hospital-based case–control study (221 HPC cases and 560 controls) | HPC (≥2 first-degree affected family members) | A | ORhom/het = 1.70 (1.02–2.84) | 0.04 | Sun J. et al., 2008 (32) | Model adjusted for age |
aPosition based on NCBI Build 36.
Discussion
To date, GWAS have identified more than 30 potential prostate cancer susceptibility variants primarily in the 8q24 chromosomal region as well as on chromosomes 3, 7, 17, 22, and X (6, 35). This review presents SNPs that were originally identified in GWAS conducted primarily in populations of European descent and in sporadic prostate cancer cases and subsequently replicated in populations at higher risk for developing prostate cancer, including men of African descent and men with FPC/HPC. We chose to focus on replicated SNPs in high-risk men, as these men stand to gain greater benefit by further validation of these replicated SNPs to assess the magnitude of risk for developing prostate cancer and elucidating the function and clinical utility of replicated SNPs to inform future decision making for prostate cancer early detection and prevention. This review finds a promising rate of replication of GWAS SNPs particularly in men of African descent and modest replication in men with FPC/HPC. Indeed, 63% of GWAS SNPs had replicated associations with prostate cancer in men of African descent and 33% of the GWAS SNPs had associations with prostate cancer in men with FPC/HPC. A recent meta-analysis of replicated SNPs from GWAS also identified 31 SNPs to have significant associations with prostate cancer. (36). A subgroup analysis from this study revealed 4 SNPs to have significant associations with prostate cancer among men of African descent (rs10486567, rs5945572, rs5945619, and rs7931342). Of note, our review also found these SNPs to have significant associations with prostate cancer among men of African descent in 1 to 3 replication studies. Our review identifies several other SNPs with replicated associations with prostate cancer in men of African descent that deserve further study for causal gene/variant identification and potential clinical utility in prostate cancer risk assessment. Furthermore, our review is the first with an additional focus on replicated SNPs in men with FPC/HPC that also deserve study among men of African descent, as a positive family history of prostate cancer significantly increases the risk for developing this disease (37).
The rapid increase in GWAS has led to the identification of many loci that are potentially associated with disease. Replication studies are crucial to confirm associations with disease and drive next steps in elucidating disease mechanisms. Replication of associations with disease are needed to exclude potential false-positive results from initial GWAS, assess application in diverse ethnic populations, and assess associations with heterogeneity in disease phenotypes, particularly for complex diseases such as prostate cancer (38). Ultimately, the functional consequence of these replicated variants needs to be identified to accurately incorporate genetic markers into clinical decision making.
The majority of SNPs with replicated associations with prostate cancer in men of African descent and men with FPC/HPC are in the 8q24 region. These results are further supported by whole-genome admixture mapping carried out in African American men with prostate cancer that found a 3.8-Mb interval on chromosome 8q24 to be significantly associated with prostate cancer risk with a logarithm of odds (LOD) score of 7.1 (39). The 8q24 variants presented here are primarily located within this interval. The 8q24 chromosomal region is the most common region implicated in prostate cancer susceptibility and is relatively gene poor (22). Although no well-annotated genes lie within the regions of 8q24, the independent associated variants may be regulating the expression patterns of a single gene or multiple genes involved in cancer tumorigenesis and/or progression in various tissue types. The proto-oncogene MYC lies downstream of this gene desert, raising the possibility that the associated regions of risk may be involved in long-range regulation of MYC expression (40). One study evaluated the association between germ line risk variants at 8q24 and transcript levels of multiple genes, focusing on the proto-oncogene MYC. No evidence was found for changes in MYC expression levels in prostate tumor based on carrying 8q24 germ line risk variants (41). Somatic genetic studies have found the 8q24 region to be amplified in prostate tumors, which fosters continued interest in elucidating the biological mechanisms of the 8q24 region in prostate cancer risk (42).
In populations with weaker LD structures, the likelihood of finding an association between disease trait and a causal variant is increased. LD occurs in smaller blocks in individuals of African descent than in individuals of European descent (43). Examination of a 92-kb LD block in chromosome 8q24 in the Nigerian (YRI) HapMap sample revealed both greater genetic diversity and weaker LD in the YRI sample than in populations of European ancestry (24). Greater genetic diversity in African populations could make it potentially easier to uncover the yet unknown functional prostate cancer risk variants located on chromosome 8q24 or associated with the 8q24 region. For example, among a population of individuals of African descent in the southwest United States (HapMap ASW), rs16901979 was found to be in high LD with rs1551512, a SNP that was found to be associated with prostate cancer aggressiveness in a predominantly European population (44). Interestingly, the magnitude of association with prostate cancer was greater for a few 8q24 SNPs in men with FPC/HPC than for African American men in this review. This observation deserves further formal study and may have impact on clinical risk management based upon future study findings.
The functional significance of several other replicated variants outside of the 8q24 region is not fully understood, though research is ongoing to gain insights into causality to prostate cancer. Rs10486567 was found to be associated with biochemical recurrence and with castrate-resistant metastases in men of Ashkenazi Jewish descent (45). Rs10486567 is located in JAZF1. The JAZF1 gene seems to act as a transcriptional repressor of NR2C2, a nuclear orphan receptor that is expressed in prostate cancer tissue (12). However, there is yet no biological explanation for the functional implications for JAZF1 or rs10486567 in prostate carcinogenesis. rs5945619 and rs5945572 in chromosome Xp11.22 are downstream and upstream, respectively, of the NUDT11 gene. However, the NUDT11 gene has not been described as having functional significance in prostate cancer. rs4430796 located in the HFN1B gene, is involved in organ development and regulation of the expression of multiple genes (46, 47). Marker rs1859962 lies within a strong LD block within 17q24.3, the functional significance of which is unclear (27). rs2735839 is located between the prostate protease genes KLK2 and KLK3 and has also been associated with prostate cancer–specific survival (45). Both rs7931342 and rs10896449 at 11q13 are located in a gene-poor region. rs10896449 has been found to be significantly associated with prostate cancer risk in a GWAS and confirmed in a study of 4 primarily Caucasian populations (12, 48). rs10993994 is located near MSMB (beta-microseminoprotein), which encodes a product (PSP94) that at lower levels is associated with more aggressive prostate cancer (49). Recently, rs10993994 has also been reported to be associated with prostate cancer recurrence and metastasis (50). Dedicated approaches with newer technologies, including fine mapping and next generation sequencing, hold promise for honing in on causal genetic variants in loci identified by GWAS/replicated SNPs or identify genetic/epigenetic mechanisms contributing to the development of prostate cancer.
This review focused on SNPs originally found to be associated with prostate cancer from GWAS and then replicated in men at increased risk for developing prostate cancer. Additional markers have been reported to be associated with prostate cancer at 8q24 particularly in men of African descent that were not originally identified in GWAS based in European populations. These include rs7008482 (11, 14, 16), rs4871005 (11, 14), rs6981122 (11, 14), and bd11934905 (21, 26, 51). These markers also hold promise for further study of clinical utility in prostate cancer risk assessment. In addition, a recent GWAS conducted in an African American population revealed SNP rs7210100 on chromosome 17q21 to be significantly associated with prostate cancer (OR = 1.51, P = 3.4 × 10−13; 8). This marker is located in intron 1 of ZNF652, which encodes a zinc-finger protein transcription factor that interacts with corepressor proteins and histone deacetylases (HDAC; ref. 52) However, the function of this variant or link to a causal variant for prostate cancer susceptibility remains to be determined.
In summary, we find a promising rate of replication of prostate cancer–associated SNPs from GWAS in men of African descent and men with FPC/HPC. Although the biological mechanisms and potentially causal variants have yet to be fully defined, the consistent associations of the SNPs in this review provide greater support for validation studies of these replicated variants in high-risk men, give potential for identifying novel prostate cancer–related genes, and support efforts to elucidate the functional consequence of these variants. Ultimately, the study of the clinical utility of these markers for prostate cancer screening and prevention among high-risk men is warranted.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Acknowledgments
Funding support (VNG): Department of Defense Prostate Cancer Research Program Physician Research Training Award (W81XWH-09-1-0302).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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