Replication of Prostate Cancer Risk Variants in a Danish Case-Control Association Study

DOI: 10.4236/oju.2012.22009   PDF   HTML     3,201 Downloads   6,226 Views   Citations


Background: Prostate cancer is one of the main causes for cancer morbidity and mortality in Western countries. Recently, several single nucleotide polymorphisms (SNPs) associated with prostate cancer have been identified in genome-wide association studies and multiple variant models have been developed to predict prostate cancer risk. The association between genetic markers and clinico-pathological tumor variables has, however, been inconsistent. Methods and Materials: A total of 32 previously identified prostate cancer-associated risk SNPs were genotyped in 648 prostate cancer cases and 526 age-matched controls. Family history was obtained by questionnaire. Age at diagnosis, clinical tumor variables including pre- and postoperative PSA, Gleason score, and T stage were obtained from prospectively collected clinical data (Aarhus Prostate Cancer Study). The SNPs were genotyped using Sequenom and Taqman assays and associations between SNPs, prostate cancer risk, and clinico-pathological variables were assessed. Results: Seventeen SNPs were successfully replicated in our case-control study and the association estimates were consistent with previous reports. Four markers were excluded from further analysis due to linkage disequilibrium. The cumulative effect of having the disease-associated genotype at five SNPs (rs4430796, rs6983267, rs1859962, rs1447295 and rs16901979) increased the prostate cancer risk with odds ratio 6.02 (95% CI: 2.21 - 16.38; P = 1.0 × 10–4) in patients with any combination of ≥4 markers compared with patients without any of the five SNPs (P for trend = 1.0 × 10–4). Six markers were significantly associated with clinico-pathological variables: SNP rs2735839 (GG) at locus 19q13, which is in the KLK3 gene encoding PSA, was associated with high preoperative PSA (P = 0.04), low Gleason score (P = 0.01) and low T stage (P = 0.02). Variants rs5759167 (GG/GT) (22q13) and rs7679673 (CC/CA) (4q24) were correlated with low risk for biochemical relapse (P = 0.015 and P = 0.009, respectively), whereas rs6983267 (GG) (8q24) was significantly associated with biochemical recurrence (P = 0.045). In addition, variants rs6983267 (GG) and rs5759167 (GG/GT) were significantly associated with negative family history (P = 0.04 and P = 0.02, respectively). Conclusion: We replicated 17 previously identified prostate cancer-associated risk SNPs in a Danish case-control study and found a cumulative and significant association between five SNPs and prostate cancer. Overall, we noted significant associations between several prostate cancer-associated risk genotypes and less aggressive tumor variables, high level of PSA, and low risk for biochemical reccurrence.

Share and Cite:

D. Nguyen Bentzon, M. Nyegaard, A. Børglum, T. Ørntoft, M. Borre and K. Dalsgaard Sørensen, "Replication of Prostate Cancer Risk Variants in a Danish Case-Control Association Study," Open Journal of Urology, Vol. 2 No. 2, 2012, pp. 45-54. doi: 10.4236/oju.2012.22009.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] A. Jemal, M. M. Center, C. DeSantis and E. M. Ward, “Global Patterns of Cancer Incidence and Mortality Rates and Trends,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 19, 2010, pp. 1893-1907.
[2] J. Ferlay, H. R. Shin, F. Bray, D. Forman, C. Mathers and D. M. Parkin, “Estimates of Worldwide Burden of Cancer in 2008: GLOBOCAN 2008,” International Journal of Cancer, Vol. 127, No. 12, 2010, pp. 2893-2917.
[3] W. F. Page, M. M. Braun, A. W. Partin, N. Caporaso and P. Walsh, “Heredity and Prostate Cancer: A Study of World War II Veteran Twins,” The Prostate, Vol. 33, No. 4, 1997, pp. 240-245. doi:10.1002/(SICI)1097-0045(19971201)33:4<240::AID-PROS3>3.0.CO;2-L
[4] M. P. Zeegers, A. Jellema and H. Ostrer, “Empiric Risk of Prostate Carcinoma for Relatives of Patients with Prostate Carcinoma: A Meta-Analysis,” Cancer, Vol. 97, No. 8, 2003, pp. 1894-1903. doi:10.1002/cncr.11262
[5] B. S. Carter, G. S. Bova, T. H. Beaty, et al., “Hereditary Prostate Cancer: Epidemiologic and Clinical Features,” The Journal of Urology, Vol. 150, No. 3, 1993, pp. 797-802.
[6] P. A. Kupelian, V. A. Kupelian, J. S. Witte, R. Macklis and E. A. Klein, “Family History of Prostate Cancer in Patients with Localized Prostate Cancer: An Independent Predictor of Treatment Outcome,” Journal of Clinical Oncology, Vol. 15, No. 4, 1997, pp. 1478-1480.
[7] G. S. Bova, A. W. Partin, S. D. Isaacs, et al., “Biological Aggressiveness of Hereditary Prostate Cancer: Long-Term Evaluation Following Radical Prostatectomy,” The Journal of urology, Vol. 160, No. 3, 1998, pp. 660-663. doi:10.1016/S0022-5347(01)62748-4
[8] A. Valeri, R.Azzouzi, E. Drelon, et al., “Early-Onset Hereditary Prostate Cancer Is Not Associated with Specific Clinical and Biological Features,” The Prostate, Vol. 45, No. 1, 2000, pp. 66-71. doi:10.1002/1097-0045(20000915)45:1<66::AID-PROS8>3.0.CO;2-W
[9] O. Bratt, J. E. Damber, M. Emanuelsson and H. Gronberg, “Hereditary Prostate Cancer: Clinical Characteristics and Survival,” The Journal of Urology, Vol. 167, No. 6, 2002, pp. 2423-2426. doi:10.1016/S0022-5347(05)64997-X
[10] S. V. Kotsis, S. L. Spencer, P. A. Peyser, J. E. Montie and K. A. Cooney, “Early Onset Prostate Cancer: Predictors of Clinical Grade,” The Journal of Urology, Vol. 167, No. 4, 2002, pp. 1659-1663. doi:10.1016/S0022-5347(05)65173-7
[11] E. Sacco, T. Prayer-Galetti, F. Pinto, et al., “Familial and Hereditary Prostate Cancer by Definition in an Italian Surgical Series: Clinical Features and Outcome,” European Urology, Vol. 47, No. 6, 2005, pp. 761-768. doi:10.1016/j.eururo.2005.01.016
[12] E. Spangler, C. M. Zeigler-Johnson, S. B. Malkowicz, A. J. Wein and T. R. Rebbeck, “Association of Prostate Cancer Family History with Histopathological and Clinical Characteristics of Prostate Tumors,” International Journal of Cancer, Vol. 113, No. 3, 2005, pp. 471-474.
[13] S. Pakkanen, P. M. Kujala, N. Ha, M. P. Matikainen, J. Schleutker and T. L. Tammela, “Clinical and Histopathological Characteristics of Familial Prostate Cancer in Finland,” BJU International, Vol. 109, No. 4, 2011, pp. 557-563.
[14] J. P. Ioannidis, P. Castaldi and E. Evangelou, “A Compendium of Genome-Wide Associations for Cancer: Critical Synopsis and Reappraisal,” Journal of the National Cancer Institute, Vol. 102, No. 12, 2010, pp. 846-858. doi:10.1093/jnci/djq173
[15] S. T. Kim, Y. Cheng, F. C. Hsu, et al., “Prostate Cancer Risk-Associated Variants Reported from Genome-Wide Association Studies: Meta-Analysis and Their Contribution to Genetic Variation,” The Prostate, Vol. 70, No. 16, 2010, pp. 1729-1738.
[16] Z. Kote-Jarai, A. A. Olama, G. G. Giles, et al., “Seven Prostate Cancer Susceptibility Loci Identified by a MultiStage Genome-Wide Association Study,” Nature Genetics, Vol. 43, No. 8, 2011, pp. 785-791. doi:10.1038/ng.882
[17] J. Beuten, J. A. Gelfond, J. L. Franke, et al., “Single and Multigenic Analysis of the Association between Variants in 12 Steroid Hormone Metabolism Genes and Risk of Prostate Cancer,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 18, No. 6, 2009, pp. 1869-1880.
[18] F. C. Hsu, J. Sun, Y. Zhu, et al., “Comparison of Two Methods for Estimating Absolute Risk of Prostate Cancer Based on Single Nucleotide Polymorphisms and Family History,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 19, No. 4, 2010, pp. 1083-1088.
[19] M. Aly, F. Wiklund, J. Xu, et al., “Polygenic Risk Score Improves Prostate Cancer Risk Prediction: Results from the Stockholm-1 Cohort Study,” European urology, Vol. 60, No. 1, 2011, pp. e1-e8. doi:10.1016/j.eururo.2011.01.017
[20] L. M. Fitzgerald, E. M. Kwon, J. S. Koopmeiners, C. A. Salinas, J. L. Stanford and E. A. Ostrander, “Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-Based Study: Associations with Family History and Clinical Features,” Clinical Cancer Research, Vol. 15, No. 9, 2009, pp. 3231-3237.
[21] N. J. Camp, J. M. Farnham, J. Wong, G. B. Christensen, A. Thomas and L. A. Cannon-Albright, “Replication of the 10q11 and Xp11 Prostate Cancer Risk Variants: Results from a Utah Pedigree-Based Study,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 18, No. 4, 2009, pp. 1290-1294.
[22] V. D’Amico, R. Whittington, S. B. Malkowicz, et al., “Biochemical Outcome after Radical Prostatectomy, External Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer,” The Journal of the American Medical Association, Vol. 280, No. 11, 1998, pp. 969-974. doi:10.1001/jama.280.11.969
[23] H. R. Andersen, T. T. Nielsen, T. Vesterlund, et al., “Danish Multicenter Randomized Study on Fibrinolytic Therapy versus Acute Coronary Angioplasty in Acute Myocardial Infarction: Rationale and Design of the Danish Trial in Acute Myocardial Infarction-2 (DANAMI-2),” American Heart Journal, Vol. 146, No. 2, 2003, pp. 234-241. doi:10.1016/S0002-8703(03)00316-8
[24] M. L. Freedman, C. A. Haiman, N. Patterson, et al., “Admixture Mapping Identifies 8q24 as a Prostate Cancer Risk Locus in African-American Men,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 38, 2006, pp. 14068-14073. doi:10.1073/pnas.0605832103
[25] L. T. Amundadottir, P. Sulem, J. Gudmundsson, et al., “A Common Variant Associated with Prostate Cancer in European and African Populations,” Nature Genetics, Vol. 38, No. 6, 2006, pp. 652-658. doi:10.1038/ng1808
[26] D. Duggan, S. L. Zheng, M. Knowlton, et al., “Two Genome-Wide Association Studies of Aggressive Prostate Cancer Implicate Putative Prostate Tumor Suppressor Gene DAB2IP,” Journal of the National Cancer Institute, Vol. 99, No. 24, 2007, pp. 1836-1844. doi:10.1093/jnci/djm250
[27] J. Gudmundsson, P. Sulem, V. Steinthorsdottir, et al., “Two Variants on Chromosome 17 Confer Prostate Cancer Risk, and the One in TCF2 Protects against Type 2 Diabetes,” Nature Genetics, Vol. 39, No. 8, 2007, pp. 977-983. doi:10.1038/ng2062
[28] J. Gudmundsson, P. Sulem, A. Manolescu, et al., “Genome-Wide Association Study Identifies a Second Prostate Cancer Susceptibility Variant at 8q24,” Nature Genetics, Vol. 39, No. 5, 2007, pp. 631-637. doi:10.1038/ng1999
[29] C. A. Haiman, N. Patterson, M. L. Freedman, et al., “Multiple Regions within 8q24 Independently Affect Risk for Prostate Cancer,” Nature Genetics, Vol. 39, No. 5, 2007, pp. 638-644. doi:10.1038/ng2015
[30] M. Yeager, N. Orr, R. B. Hayes, et al., “Genome-Wide Association Study of Prostate Cancer Identifies a Second Risk Locus at 8q24,” Nature Genetics, Vol. 39, No. 5, 2007, pp. 645-649. doi:10.1038/ng2022
[31] S. L. Zheng, J. Sun, Y. Cheng, et al., “Association between Two Unlinked Loci at 8q24 and Prostate Cancer Risk among European Americans,” Journal of the National Cancer Institute, Vol. 99, No. 20, 2007, pp. 1525-1533. doi:10.1093/jnci/djm169
[32] R. A. Eeles, Z. Kote-Jarai, G. G. Giles, et al., “Multiple Newly Identified Loci Associated with Prostate Cancer Susceptibility,” Nature Genetics, Vol. 40, No. 3, 2008, pp. 316-321. doi:10.1038/ng.90
[33] J. Gudmundsson, P. Sulem, T. Rafnar, et al., “Common Sequence Variants on 2p15 and Xp11.22 Confer Susceptibility to Prostate Cancer,” Nature genetics, Vol. 40, No. 10, 2008, pp. 281-283. doi:10.1038/ng.89
[34] G. Thomas, K. B. Jacobs, M. Yeager, et al., “Multiple Loci Identified in a Genome-Wide Association Study of Prostate Cancer,” Nature Genetics, Vol. 40, No. 3, 2008, pp. 310-315. doi:10.1038/ng.91
[35] A. Al Olama, Z. Kote-Jarai, G. G. Giles, et al., “Multiple Loci on 8q24 Associated with Prostate Cancer Susceptibility,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1058-1060. doi:10.1038/ng.452
[36] R. A. Eeles, Z. Kote-Jarai, A. A. Al Olama, et al., “Identification of Seven New Prostate Cancer Susceptibility Loci through a Genome-Wide Association Study,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1116-1121. doi:10.1038/ng.450
[37] J. Gudmundsson, P. Sulem, D. F. Gudbjartsson, et al., “Genome-Wide Association and Replication Studies Identify Four Variants Associated with Prostate Cancer Susceptibility,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1122-1126. doi:10.1038/ng.448
[38] M. Yeager, N. Chatterjee, J. Ciampa, et al., “Identification of a New Prostate Cancer Susceptibility Locus on Chromosome 8q24,” Nature Genetics, Vol. 41, No. 10, 2009, pp. 1055-1057. doi:10.1038/ng.444
[39] W. Y. Wang, B. J. Barratt, D. G. Clayton and J. A. Todd, “Genome-Wide Association Studies: Theoretical and Practical Concerns,” Nature Reviews Genetics, Vol. 6, No. 2, 2005, pp. 109-118. doi:10.1038/nrg1522
[40] S. Purcell, B. Neale, K. Todd-Brown, et al., “PLINK: A Tool Set for Whole-Genome Association and PopulationBased Linkage Analyses,” American Journal of Human Genetics, Vol. 81, No. 3, 2007, pp. 559-575. doi:10.1086/519795
[41] S. L. Zheng, J. Sun, F. Wiklund, et al., “Cumulative Association of Five Genetic Variants with Prostate Cancer,” The New England Journal of Medicine, Vol. 358, No. 9, 2008, pp. 910-919. doi:10.1056/NEJMoa075819
[42] A. K. Kader, J. Sun, S. D. Isaacs, et al., “Individual and Cumulative Effect of Prostate Cancer Risk-Associated Variants on Clinicopathologic Variables in 5895 Prostate Cancer Patients,” The Prostate, Vol. 69, No. 11, 2009, pp. 1195-1205. doi:10.1002/pros.20970
[43] M. M. Pomerantz, L. Werner, W. Xie, et al., “Association of Prostate Cancer Risk Loci with Disease Aggressiveness and Prostate Cancer-Specific Mortality,” Cancer Prevention Research, Vol. 4, No. 5, 2011, pp. 719-728. doi:10.1158/1940-6207.CAPR-10-0292
[44] C. A. Salinas, J. S. Koopmeiners, E. M. Kwon, et al., “Clinical Utility of Five Genetic Variants for Predicting Prostate Cancer Risk and Mortality,” The Prostate, Vol. 69, No. 4, 2009, pp. 363-372. doi:10.1002/pros.20887
[45] J. Sun, B. L. Chang, S. D. Isaacs, et al., “Cumulative Effect of Five Genetic Variants on Prostate Cancer Risk in Multiple Study Populations,” The Prostate, Vol. 68, No. 12, 2008, pp. 1257-1262. doi:10.1002/pros.20793
[46] J. Xu, S. D. Isaacs, J. Sun, et al., “Association of Prostate Cancer Risk Variants with Clinicopathologic Characteristics of the Disease,” Clinical Cancer Research, Vol. 14, No. 18, 2008, pp. 5819-5824.
[47] K. L. Penney, F. R. Schumacher, P. Kraft, et al., “Association of KLK3 (PSA) Genetic Variants with Prostate Cancer Risk and PSA Levels,” Carcinogenesis, Vol. 32, No. 6, 2011, pp. 853-859. doi:10.1093/carcin/bgr050
[48] P. I. Lin, J. M. Vance, M. A. Pericak-Vance and E. R. Martin, “No Gene Is an Island: The Flip-Flop Phenomenon,” American Journal of Human Genetics, Vol. 80, No. 3, 2007, pp. 531-538. doi:10.1086/512133
[49] H. Schunkert, I. R. Konig, S. Kathiresan, et al., “LargeScale Association Analysis Identifies 13 New Susceptibility Loci for Coronary Artery Disease,” Nature Genetics, Vol. 43, No. 4, 2011, pp. 333-338. doi:10.1038/ng.784

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.