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The Usefulness of Prostate Cancer Genome-Wide Association Studies
The Usefulness of Prostate Cancer Genome-Wide Association Studies SINCE 2007 more than 1,200 genome-wide association studies (GWASs) have been published identifying single nucleotide polymorphisms (SNPs) associated with various traits and diseases including complex diseases such as prostate cancer (PCa). A PubMed search with “GWAS” as a keyword yielded 1,348 hits in August 2011. The perceived usefulness of such studies is twofold, generating risk assessment through associated SNPs and providing insight into novel disease mechanisms. While challenges exist in demonstrating this usefulness, with recent advances there is optimism that the considerable investments into GWAS will pay dividends. Risk loci of PCa at chromosome 8q24 are examples of where risk assessments and disease mechanisms have been revealed. Risk Assessments at 8q24 Loci associated with disease, as revealed by GWAS, may be used individually or in combination in risk prediction. In the example of PCa, risk loci in 5 blocks at 8q24 have been identified that independently impose risk.1,2 However, most of the GWASs conducted to date have been performed in populations of patients of white European ancestry. If variation in linkage disequilibrium patterns is responsible for signal heterogeneity among populations, then the expectation is that the biologically relevant SNPs will be more strongly associated with risk across multiple populations (each population has a different linkage disequilibrium structure at a particular locus). Thus, variants may be designated as putative causal ones if consistently imposing risk in multiple populations. A step toward this goal is presented by Liu et al in this issue of the Journal (page 315), in a study in which risk SNPs at 8q24 were associated with PCa in northern Chinese men. In this study 4 of 15 SNPs were associated with PCa risk, indicating that they may more closely define causal alleles. Although this study was relatively small (256 cases and 288 controls), it was highly informative. Risk alleles at 8q24 were found in some known PCa risk regions but not in others. 0022-5347/12/1871-0009/0 THE JOURNAL OF UROLOGY® © 2012 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION
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RESEARCH, INC.
In a recent, larger study of PCa in African-American men (3,425 prostate cancer cases and 3,290 controls) fine mapping identified 9 SNPs at 8q24 that best captured the risk of prostate cancer in this group.3 Many of these SNPs are more common in men of African than European descent, providing a genetic explanation for the higher risk of PCa in African-American men. A major dilemma in managing PCa is that most diagnosed cancers do not progress to clinically relevant disease. However, those that do progress often result in fatal consequences. Biomarkers of advanced disease remain elusive. Since there does not seem to be any strong, nongenetic predisposition factor for this disease, the identification of genetic profiles that act as biomarkers of clinically relevant PCa would facilitate earlier intervention with modalities such as preventive chemotherapy. For example, by considering PCa risk SNPs along with prostate specific antigen, increased risk predictability compared to prostate specific antigen levels alone was evident.4 Although most GWAS signals identified to date do not mark advanced disease, perhaps due to study design issues, Liu et al provide the first indications that SNPs at 8q24 may be informative in this regard. Thus, rs16901966 was associated with aggressive PCa, whereas rs16901966, rs1447295 and rs10090154 were associated with tumor stage. Disease Mechanisms at 8q24 Most SNPs tagging complex diseases reside in noncoding regions of the genome. Thus, their functional consequences are not immediately obvious. A road map of how to gain insight into the functionality of such SNPs was recently formulated.5 Despite difficulties in assigning a priori functionality to such noncoding SNPs, mechanisms revealed by the functional annotation of such SNPs will open unexpected avenues of investigation in PCa etiology because the original GWASs were performed agnostically. Novel biological mechanisms will illuminate genes/pathways involved in PCa that may, in turn, become potential targets for therapy. Chromosome 8q24 risk Vol. 187, 9-10, January 2012 Printed in U.S.A. DOI:10.1016/j.juro.2011.10.057
www.jurology.com
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GENOME-WIDE ASSOCIATION STUDIES AND PROSTATE CANCER RISK
regions are good examples of where significant mechanistic progress has been made. Recently an integrated framework was developed based on chromatin structure and transcription factor binding to allow noncoding loci (as found at 8q24) to be annotated with respect to putative enhancers. Based on histone H3 acetylation peaks and androgen receptor occupied regions, enhancers were identified in this region6,7 that included how they loop to the potent oncogene c-Myc, some 200-400 kb telomeric from the 8q24 risk regions.8 Differential transcription factor binding to the different alleles (FoxA16 at the one enhancer and TCF7L27 at the other enhancer) resulted in the modulation of their enhancer activities. This provided mechanistic explanations of how the risk effects are brought about as originally revealed in GWAS. Conclusions Although the usefulness of GWAS has been questioned,9 it has been argued that we ought not give up on such approaches as they provide a unique vantage point for the elucidation of potentially forthcoming and reliable risk assessments as well as
discoveries of disease mechanisms.10 An era of personalized medicine may be more realistic than originally anticipated for complex genetic diseases. GWASs were the first steps toward this goal and post-GWAS investigations should now follow as the next steps, which should include fine mapping and functional annotation. Technical advances such as next generation sequencing are facilitating these investigations and even individual whole genome sequencing is probably not too far into the future. The major bottleneck may soon be neither technical nor cost based (as is presently the case), but rather related to bioinformatic capabilities for in-depth analysis and interpretation of the massive data streams being generated. Thus, the development of bioinformatic approaches is of the highest priority at most genomic/genetic research institutions. Gerhard A. Coetzee Departments of Urology and Preventive Medicine USC/Norris Cancer Center Keck School of Medicine University of Southern California Los Angeles, California
REFERENCES 1. Al Olama AA, Kote-Jarai Z, Giles GG et al: Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 2009; 41: 1058. 2. Haiman CA, Patterson N, Freedman ML et al: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 2007; 39: 638. 3. Haiman CA, Chen GK, Blot WJ et al: Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet 2011; 7: e1001387.
4. Loeb S, Carter HB, Walsh PC et al: Single nucleotide polymorphisms and the likelihood of prostate cancer at a given prostate specific antigen level. J Urol 2009; 182: 101. 5. Freedman ML, Monteiro AN, Gayther SA et al: Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 2011; 43: 513. 6. Jia L, Landan G, Pomerantz M et al: Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 2009; 5: e1000597.
7. Pomerantz MM, Ahmadiyeh N, Jia L et al: The 8q24 cancer risk variant rs6983267 shows longrange interaction with MYC in colorectal cancer. Nat Genet 2009; 41: 882. 8. Ahmadiyeh N, Pomerantz MM, Grisanzio C et al: 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 2010; 107: 9742. 9. Dermitzakis ET and Clark AG: Genetics. Life after GWA studies. Science 2009; 326: 239. 10. Sullivan P: Don’t give up on GWAS. Mol Psychiatry, Epub ahead of print Aug 9, 2011.
AND
RESEARCH, INC.
In a recent, larger study of PCa in African-American men (3,425 prostate cancer cases and 3,290 controls) fine mapping identified 9 SNPs at 8q24 that best captured the risk of prostate cancer in this group.3 Many of these SNPs are more common in men of African than European descent, providing a genetic explanation for the higher risk of PCa in African-American men. A major dilemma in managing PCa is that most diagnosed cancers do not progress to clinically relevant disease. However, those that do progress often result in fatal consequences. Biomarkers of advanced disease remain elusive. Since there does not seem to be any strong, nongenetic predisposition factor for this disease, the identification of genetic profiles that act as biomarkers of clinically relevant PCa would facilitate earlier intervention with modalities such as preventive chemotherapy. For example, by considering PCa risk SNPs along with prostate specific antigen, increased risk predictability compared to prostate specific antigen levels alone was evident.4 Although most GWAS signals identified to date do not mark advanced disease, perhaps due to study design issues, Liu et al provide the first indications that SNPs at 8q24 may be informative in this regard. Thus, rs16901966 was associated with aggressive PCa, whereas rs16901966, rs1447295 and rs10090154 were associated with tumor stage. Disease Mechanisms at 8q24 Most SNPs tagging complex diseases reside in noncoding regions of the genome. Thus, their functional consequences are not immediately obvious. A road map of how to gain insight into the functionality of such SNPs was recently formulated.5 Despite difficulties in assigning a priori functionality to such noncoding SNPs, mechanisms revealed by the functional annotation of such SNPs will open unexpected avenues of investigation in PCa etiology because the original GWASs were performed agnostically. Novel biological mechanisms will illuminate genes/pathways involved in PCa that may, in turn, become potential targets for therapy. Chromosome 8q24 risk Vol. 187, 9-10, January 2012 Printed in U.S.A. DOI:10.1016/j.juro.2011.10.057
www.jurology.com
9
10
GENOME-WIDE ASSOCIATION STUDIES AND PROSTATE CANCER RISK
regions are good examples of where significant mechanistic progress has been made. Recently an integrated framework was developed based on chromatin structure and transcription factor binding to allow noncoding loci (as found at 8q24) to be annotated with respect to putative enhancers. Based on histone H3 acetylation peaks and androgen receptor occupied regions, enhancers were identified in this region6,7 that included how they loop to the potent oncogene c-Myc, some 200-400 kb telomeric from the 8q24 risk regions.8 Differential transcription factor binding to the different alleles (FoxA16 at the one enhancer and TCF7L27 at the other enhancer) resulted in the modulation of their enhancer activities. This provided mechanistic explanations of how the risk effects are brought about as originally revealed in GWAS. Conclusions Although the usefulness of GWAS has been questioned,9 it has been argued that we ought not give up on such approaches as they provide a unique vantage point for the elucidation of potentially forthcoming and reliable risk assessments as well as
discoveries of disease mechanisms.10 An era of personalized medicine may be more realistic than originally anticipated for complex genetic diseases. GWASs were the first steps toward this goal and post-GWAS investigations should now follow as the next steps, which should include fine mapping and functional annotation. Technical advances such as next generation sequencing are facilitating these investigations and even individual whole genome sequencing is probably not too far into the future. The major bottleneck may soon be neither technical nor cost based (as is presently the case), but rather related to bioinformatic capabilities for in-depth analysis and interpretation of the massive data streams being generated. Thus, the development of bioinformatic approaches is of the highest priority at most genomic/genetic research institutions. Gerhard A. Coetzee Departments of Urology and Preventive Medicine USC/Norris Cancer Center Keck School of Medicine University of Southern California Los Angeles, California
REFERENCES 1. Al Olama AA, Kote-Jarai Z, Giles GG et al: Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 2009; 41: 1058. 2. Haiman CA, Patterson N, Freedman ML et al: Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet 2007; 39: 638. 3. Haiman CA, Chen GK, Blot WJ et al: Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet 2011; 7: e1001387.
4. Loeb S, Carter HB, Walsh PC et al: Single nucleotide polymorphisms and the likelihood of prostate cancer at a given prostate specific antigen level. J Urol 2009; 182: 101. 5. Freedman ML, Monteiro AN, Gayther SA et al: Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 2011; 43: 513. 6. Jia L, Landan G, Pomerantz M et al: Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 2009; 5: e1000597.
7. Pomerantz MM, Ahmadiyeh N, Jia L et al: The 8q24 cancer risk variant rs6983267 shows longrange interaction with MYC in colorectal cancer. Nat Genet 2009; 41: 882. 8. Ahmadiyeh N, Pomerantz MM, Grisanzio C et al: 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 2010; 107: 9742. 9. Dermitzakis ET and Clark AG: Genetics. Life after GWA studies. Science 2009; 326: 239. 10. Sullivan P: Don’t give up on GWAS. Mol Psychiatry, Epub ahead of print Aug 9, 2011.