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Published online before print
October 31, 2007, 10.1101/gr.6782707 Genome Res. 17:1717-1722, 2007 ©2007 by Cold Spring Harbor Laboratory Press; ISSN 1088-9051/07 $5.00
Letter Confirmation study of prostate cancer risk variants at 8q24 in African Americans identifies a novel risk locus1 Division of Integrated Cancer Genomics, Translational Genomics Research Institute, Phoenix, Arizona 85004, USA; 2 Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Ilinois 60637, USA; 3 Department of Clinical Pharmacology, University of Oxford, Oxford, OX2 6HA, UK; 4 Division of Urology, Howard University Hospital, Washington, District of Columbia 20060, USA
Prostate cancer is a common complex disease that disproportionately affects men of African descent. Recently, several different common variants on chromosome 8q24 have been shown to be associated with prostate cancer in multiple studies and ethnic groups. The objective of this study was to confirm the association of 8q24 markers with prostate cancer in African Americans. We genotyped 24 markers along 8q24 and 80 unlinked ancestry informative markers in a hospital-based case-control sample of 1057 African American men (490 prostate cancer cases and 567 controls). Association analyses of 8q24 markers with prostate cancer risk were adjusted for both global and local 8q24 admixture stratification using estimates from ancestry informative markers. We report that rs7008482, which maps to the 8q24.13 region, is an additional independent prostate cancer risk variant (P = 5 x 10–4), and we also replicate the association of rs16901979 with prostate cancer (P = 0.002). Other published risk variants in the region such as rs1447295 and rs6983267 showed a similar direction and magnitude of effect, but were not significant in our population. Both rs7008482 and rs16901979 independently predicted risk and remained significant (P < 0.001) after controlling for each other. Our data combined with additional replications of 8q24 markers provide compelling support for multiple regions of risk for prostate cancer on 8q24.
Prostate cancer (PCa) still remains the most common male-specific malignancy diagnosed in the United States. In 2007 alone, about 218,890 new cases of prostate cancer and 27,050 deaths will be attributed to this disease (Jemal et al. 2007  ). This slight decrease when compared with previous annual estimates is due to a new method being utilized in estimating new cancer cases by the American Cancer Society. The new estimate covers about 86% versus the previous 10% of the US population (Jemal et al. 2007). Despite the slight decrease in the estimates for 2007, African American (AA) men still have an even higher incidence and mortality rate when compared with other ethnic groups (Jemal et al. 2007).
Genome-wide linkage and association studies have been used to identify genomic loci contributing to prostate cancer susceptibility. Recently, the results of a genome-wide scan in Icelandic families suggested strong evidence for association between a microsatellite marker at 8q24 (DG8S737) and prostate cancer risk (Amundadottir et al. 2006
In an independent study, a multiethnic cohort of prostate cancer cases and controls was evaluated with
Furthermore, results of an independent genome-wide scan in
Here, we report on a structured association analysis of the original 8q24 markers (DG8S737 and rs1447295) reported by Amundadottiir et al. (2006)
The clinical characteristics of our prostate cancer cases and controls are shown in Table 1. Cases and controls were not significantly different except for mean PSA and mean West African genetic ancestry values. Mean West African ancestry was significantly higher among the PCa cases than controls for both local 8q individual ancestry (LIA) and global individual ancestry (GIA) (P = 0.001) (Table 1).
Twenty-four of the SNPs genotyped map to human chromosome 8. Three SNPs map to 8p and the other 21 SNPs map to 8q24. We tested genotype frequencies for significant departure from Hardy Weinberg (HW) proportions independently in the cases and controls. Two SNPs were excluded; rs10086908 due to strong departure from Hardy Weinberg equilibrium (P = 1 x 10–24) and rs1668875, because it was monomorphic in our population (Supplemental Table 1). Allele frequencies for the remaining 22 SNPs are detailed in Table 2. Minor allele frequencies ranged from 6% to 42% in the African American controls.
Three SNPs mapping to 8q24.13, rs7008482, rs2124036, and rs780321, and one SNP mapping to 8q24.21, rs16901979, appeared to influence prostate cancer risk in our African American cohort after controlling for age and GIA (Table 2). To be more confident in our findings we again performed our regression analyses; however, this time we controlled for differences in locus-specific ancestry along 8q24 using the LIA estimates. We determined that the slight associations for rs2124036 and rs780321 were likely due to local admixture. Two SNPs remained significantly associated with prostate cancer even after including LIA as a covariate, rs7008482 (OR = 1.8; CI = 1.2–2.6; P = 0.002) and rs16901979 (OR = 1.5, CI = 1.1–2.2; P = 0.008) (Table 3). Table 3 details prostate cancer risk associated with polymorphisms across several regions along 8q24 in this and previous studies of African Americans. Surprisingly, there is very little linkage disequilibrium between markers in close proximity in regions 1–3 (Witte 2007 ). The two significant SNPs we observed in this study were found in region 2 (rs16901979) and a new region denoted region 4 at 126.33Mb (rs7008482).
We included two markers (rs1447295 and DG8S737) in our study to directly compare the results previously observed in African Americans by others. The microsatellite marker DG8S737 was genotyped for all 490 African American cases and 567 age- and ethnicity-matched controls. Table 4 reveals the frequencies of the 17 alleles for DG8S737 observed in the sample. While the frequencies were consistent with what was observed in the literature for African Americans, we did not observe association between any of the DG8S373 alleles and prostate cancer (P = 0.065). Also, the previously reported risk allele for SNP rs1447295 revealed no association with prostate cancer in our population (Tables 2, 3). Additionally, two SNPs within a 1.2-kb region flanking and in LD with rs1447295 were typed, rs7818556 and rs4871802, neither of which revealed an association with prostate cancer (Table 2; Fig. 1). We did observe a slight association at rs1447295 when we stratified our populations by age of diagnosis (  60; P = 0.03), similar to Schumacher et al. (2007) and Freedman et al. (2006), but when we controlled for locus-specific ancestry, the association became nonsignificant. Additionally, further analyses were carried out in which samples were stratified by family history and also pathological grade (Gleason score 7 vs.  8). We did not observe any SNP association with family history and Gleason score.
To help determine the effect size of the rs7008482 and rs16901979 SNP associations in relation to admixture effects we performed three logistic regression analyses for both markers. First we examined the SNP association unadjusted for individual ancestry, then adjusting for genome-wide ancestry, and finally controlling for genome-wide and local 8q24 individual ancestry. Assuming an additive model of effect per allele copy, the odds ratios for the three analyses were 1.89, 1.86, and 1.83, respectively, for rs7008482 and 1.52, 1.51, and 1.45, respectively, for rs16901979. Thus, ancestry effects at the genome-wide and local level contributed little if any to the rs7008482 and rs16901979 associations with prostate cancer risk. Finally, we tested the possibility of whether SNPs rs7008482 and rs16901979 could fully explain the association with prostate cancer, or whether the associations were dependent on each other. To do this we performed a stepwise regression using each SNP individually as causal while controlling for the others. No other SNPs in the region could explain the association when either rs7008482 or rs16901979 were considered causal in the analysis.
Recently, multiple independent genetic variants on chromosome region 8q24 have been implicated in prostate cancer risk (Witte 2007 ). In this study, we report on a genetic association study in 1057 African Americans for 8q24 prostate cancer risk loci. We have combined genotyping of the originally associated markers at 8q24.21 (Amundadottir et al. 2006) with genotyping of additional chromosome 8 markers, including a series of admixture informative SNPs. Neither the –8 allele at microsatellite marker DG8S737 nor SNP rs1447295 was significantly associated with prostate cancer risk in our African American cohort (Table 4). In other studies of African Americans, no significant association of prostate cancer was observed with DG8S737 (Freedman et al. 2006); however, a positive association has been reported between prostate cancer and SNP rs1447295 in an African American cohort when the data were stratified according to age (65 yr) (Schumacher et al. 2007). These results are similar to those reported by others for African Americans (Freedman et al. 2006; Gudmundsson et al. 2007). Ignoring differences in local ancestry across African American subjects may account for the differences observed in previous studies. Yet, strong and replicable association with both DG8S737 and rs1447295 are seen among cohorts of European ancestry (Schumacher et al. 2007; Severi et al. 2007; Suuriniemi et al. 2007; Wang et al. 2007). In a study of 1121 European descent familial and sporadic PCa cases, Wang et al. (2007) reported significant association with both familial (P = 0.0004) and aggressive prostate cancer (P = 0.0005) and SNP rs1447295 (Wang et al. 2007). Furthermore, positive associations were also observed for the microsatellite DG8S737 and risk of familial prostate cancer (P = 0.031) and aggressive prostate cancer (P = 0.0004) (Wang et al. 2007). In an independent study, Suuriniemi et al. (2007) reported significant association of rs1447295 with prostate cancer risk in a cohort of 597 European American prostate cancer cases and 548 matched controls. In their study, there was no evidence of association for the microsatellite DG8S737 and prostate cancer risk. Finally, in a large expanded study of both breast and prostate cancer cohorts, Schumacher et al. (2007) reported strong association of increased prostate cancer risk with rs1447295 (P = 1.23 x 10–6), primarily among European Americans. However, among African Americans, significance was achieved (P = 0.011) only for early onset cases (age <65) (Schumacher et al. 2007).
Our data validate the overall results of the previous studies, suggesting the presence of multiple independent prostate cancer susceptibility loci at 8q24. Results from a genome-wide association study on 1453 Icelandic prostate cancer cases and 3064 controls using
In our study, genotyping of additional 8q24 SNPs that show ancestral allele frequency differences implicated two separate risk loci on 8q24. Two SNPs provide evidence for 126.8 Mb and 128.4 Mb regions influencing PCa risk. SNPs rs7008482 and rs1001979 revealed a highly significant association with disease even after correction for age, and local and global individual ancestry. Therefore, the association we observe is unlikely to be biased due to admixture. Our most significantly associated SNP, rs7008482, represents a new region of independent risk (region 4), which is mapped to 8q24.13, Taken together, multiple studies, including ours, strongly support the existence of several independent susceptibility loci within the 8q24 region of the genome. While other studies reported associations within the 128–129 Mb region of 8q24, our data show an even more proximal association near position 126.2 Mb of the 8q24 region of the genome. Our data add to the continually growing body of data supporting the presence of prostate cancer risk loci at 8q24 and provide justification for further genetic investigations in this region to facilitate the identification of causal alleles. As prostate cancer disproportionately affects African Americans, the discovery of true risk alleles could have important implications for early detection of prostate cancer in this high-risk population.
Subjects Unrelated men (n = 1057) self-described as African American were recruited between the years 2001 and 2005 from the Division of Urology at Howard University Hospital (HUH) in Washington, DC. Incident prostate cancer cases (n = 490) were identified by urologists within the division or study coordinator and confirmed by review of medical records. Control subjects (n = 567) unrelated to the cases and matched for age (±5 yr) were also ascertained from the PCA screening population of the Division of Urology at HUH. Individuals who were ever diagnosed with benign prostatic hyperplasia (BPH) and/or had an elevated prostate-specific antigen test (>2.5 ng/mL), or have had an abnormal digital rectal examination (DRE) were not included as controls. The demographic characteristics of participants in the screening program were similar to the patient population seen in the Division of Urology clinics (Table 1). Recruitment of prostate cancer cases and controls occurred concurrently and were unselected with respect to family history. All participants were between 40 and 85 yr of age. Clinical characteristics including Gleason grade, PSA, age at diagnosis, and family history were obtained for all cases from medical records. Disease aggressiveness was defined as "Low" (Gleason grade <8) or "High" (Gleason grade 8). The Howard University IRB approved the study and written consent was obtained from all participants.
Genotyping
Statistical analyses
Structured association analyses
We thank all of the men who volunteered to participate in this genetic study. This research was funded in part by the National Institutes of Health (S06GM08016) and the Department of Defense (DAMD W81XWH-07-1-0203 and DAMD W81XWH-06-1-0066).
5 Corresponding author.
E-mail rkittles{at}medicine.bsd.uchicago.edu; fax (773) 702-2567. [Supplemental material is available online at www.genome.org.] Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.6782707
Amundadottir, L.T., Sulem, P., Gudmundsson, J., Helgason, A., Baker, A., Agnarsson, B.A., Sigurdsson, A., Benediktsdottir, K.R., Cazier, J.B., Sainz, J., et al. 2006. A common variant associated with prostate cancer in European and African populations. Nat. Genet. 38: 652–658.[CrossRef][Medline] El Gedaily, A., Bubendorf, L., Willi, N., Fu, W., Richter, J., Moch, H., Mihatsch, M.J., Sauter, G., and Gasser, T.C. 2001. Discovery of new DNA amplification loci in prostate cancer by comparative genomic hybridization. Prostate 46: 184–190.[CrossRef][Medline] Falush, D., Stephens, M., and Pritchard, J.K. 2003. Inference of population structure using multilocus genotype data: Linked loci and correlated allele frequencies. Genetics 164: 1567–1587. Freedman, M.L., Haiman, C.A., Patterson, N., McDonald, G.J., Tandon, A., Waliszewska, A., Penney, K., Steen, R.G., Ardlie, K., John, E.M., et al. 2006. Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc. Natl. Acad. Sci. 103: 14068–14073. Gillanders, E.M., Xu, J., Chang, B.L., Lange, E.M., Wiklund, F., Bailey-Wilson, J.E., Baffoe-Bonnie, A., Jones, M., Gildea, D., Riedesel, E., et al. 2004. Combined genome-wide scan for prostate cancer susceptibility genes. J. Natl. Cancer Inst. 96: 1240–1247. Gudmundsson, J., Sulem, P., Manolescu, A., Amundadottir, L.T., Gudbjartsson, D., Helgason, A., Rafnar, T., Bergthorsson, J.T., Agnarsson, B.A., Baker, A., et al. 2007. Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat. Genet. 39: 631–637.[CrossRef][Medline] Haiman, C.A., Patterson, N., Freedman, M.L., Myers, S.R., Pike, M.C., Waliszewska, A., Neubauer, J., Tandon, A., Schirmer, C., McDonald, G.J., et al. 2007. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat. Genet. 39: 638–644.[CrossRef][Medline] Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., and Thun, M.J. 2007. Cancer statistics, 2007. CA Cancer J. Clin. 57: 43–66. Jenkins, R.B., Qian, J., Lieber, M.M., and Bostwick, D.G. 1997. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res. 57: 524–531. Liu, W., Chang, B., Sauvageot, J., Dimitrov, L., Gielzak, M., Li, T., Yan, G., Sun, J., Sun, J., Adams, T.S., et al. 2006. Comprehensive assessment of DNA copy number alterations in human prostate cancers using Affymetrix 100K SNP mapping array. Genes Chromosomes Cancer 45: 1018–1032.[CrossRef][Medline] Potts, P.R. and Yu, H. 2005. Human MMS21/NSE2 is a SUMO ligase required for DNA repair. Mol. Cell. Biol. 25: 7021–7032. Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M.A., Bender, D., Maller, J., Sklar, P., de Bakker, P.I., Daly, M.J., et al. 2007. PLINK: A tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81: 559–575.[CrossRef][Medline] Schumacher, F.R., Feigelson, H.S., Cox, D.G., Haiman, C.A., Albanes, D., Buring, J., Calle, E.E., Chanock, S.J., Colditz, G.A., Diver, W.R., et al. 2007. A common 8q24 variant in prostate and breast cancer from a large nested case-control study. Cancer Res. 67: 2951–2956. Severi, G., Hayes, V.M., Padilla, E.J., English, D.R., Southey, M.C., Sutherland, R.L., Hopper, J.L., and Giles, G.G. 2007. The common variant rs1447295 on chromosome 8q24 and prostate cancer risk: Results from an Australian population-based case-control study. Cancer Epidemiol. Biomarkers Prev. 16: 610–612. Sun, J., Liu, W., Adams, T.S., Sun, J., Li, X., Turner, A.R., Chang, B., Kim, J.W., Zheng, S.L., Isaacs, W.B., et al. 2007. DNA copy number alterations in prostate cancers: A combined analysis of published CGH studies. Prostate 67: 692–700.[CrossRef][Medline] Suuriniemi, M., Agalliu, I., Schaid, D.J., Johanneson, B., McDonnell, S.K., Iwasaki, L., Stanford, J.L., and Ostrander, E.A. 2007. Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol. Biomarkers Prev. 16: 809–814. Tan, J.M. and Chow, V.T. 2007. Cellular expression, localization and interactions of the product of the human MOST-1 gene associated with breast and prostate cancers. Int. J. Oncol. 30: 81–89.[Medline] Tan, J.M., Tock, E.P., and Chow, V.T. 2003. The novel human MOST-1 (C8orf17) gene exhibits tissue specific expression, maps to chromosome 8q24.2, and is overexpressed/amplified in high grade cancers of the breast and prostate. Mol. Pathol. 56: 109–115. Wang, L., McDonnell, S.K., Slusser, J.P., Hebbring, S.J., Cunningham, J.M., Jacobsen, S.J., Cerhan, J.R., Blute, M.L., Schaid, D.J., and Thibodeau, S.N. 2007. Two common chromosome 8q24 variants are associated with increased risk for prostate cancer. Cancer Res. 67: 2944–2950. Witte, J.S. 2007. Multiple prostate cancer risk variants on 8q24. Nat. Genet. 39: 579–580.[CrossRef][Medline] Yeager, M., Orr, N., Hayes, R.B., Jacobs, K.B., Kraft, P., Wacholder, S., Minichiello, M.J., Fearnhead, P., Yu, K., Chatterjee, N., et al. 2007. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39: 645–649.[CrossRef][Medline]
Received June 7, 2007; accepted in revised format September 21, 2007.  CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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Abstract
Results
60 single nucletide polymorphisms (SNPs) and additional microsatellites encompassing DG8S737. Among the 37 SNPs that were associated, rs1447295 was most significant (OR = 1.72; P = 1.7 x 10–9) (Amundadottir et al. 2006
