Genetic Prostate Cancer Risk Assessment: Common Variants In 9 Genomic Regions Are Associated With Cumulative Risk

Genetic Prostate Cancer Risk Assessment: Common Variants In 9 Genomic Regions Are Associated With Cumulative Risk
Main Category: Prostate / Prostate Cancer
Also Included In: Genetics; Urology / Nephrology
Article Date: 07 Nov 2010 - 0:00 PDT

Apart from cutaneous malignancies, prostate cancer (CaP) still remains the most common cancer in men. However, the pathophysiology underlying the disease remains poorly understood and no definite behavioral or environmental risk factors have been identified. Genetics is an important, and perhaps the strongest, contributing factor to the development and progression of the disease. In fact, it has been shown that the relative risk of developing CaP is over two-fold higher in first degree relatives of affected men1. In contrast to some other cancer types, little is known about which individual genes dictate the risk of CaP. Specifically, there are only a few genes with known mutations that induce CaP, and these explain less than 10% of the risk of developing familial disease. Therefore, it is likely that variations in lower penetrance loci may contribute to disease susceptibility. Recently, multiple case-control genome wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with CaP risk. Although the initial CaP risk locus was identified along chromosome 8q24, there are now over 30 different loci located along 9 different chromosomes throughout the genome that have been discovered. However, the problem lies in how to interpret their individual and combined effects on disease risk.

Zheng and colleagues originally proposed a cumulative interaction between 5 different CaP risk loci (3 along chromosome 8q24 and 2 along chromosome 17q)2. In this study, the authors demonstrated there was an increasing risk of developing CaP associated with being a carrier of an increasing number of variant SNPs. Specifically, carriers of ≥4 of the 5 CaP risk variants had over a ~4.5 fold increased risk of developing the disease in comparison to men who carried no variants. However, since CaP risk loci continue to be discovered, the total cumulative risk associated with these variants is still unknown. Our research group recently evaluated the individual and combined effects of 9 different CaP risk loci using a population of 687 men of European ancestry with CaP and 777 controls who were similar age and race3. Individually, each locus only modestly increased the risk of being diagnosed with CaP (OR 1.2-1.7). However, when we used a cumulative model involving all 9 CaP risk loci, we found that men who were carriers of more than 6 CaP risk alleles had over a 6-fold increased risk of developing CaP compared to men who were carriers of ≤1 variants. Receiver operator curve (ROC) analyses demonstrated that this expanded model with 9 variants provided a significantly greater estimate of risk compared to one limited to the original 5 variants. However, since there are now more than 30 CaP risk loci identified, it is necessary to perform these analyses in a large population of cases and controls using all of the genetic variants. These analyses will provide a more complete understanding of their individual and cumulative risks associated with the CaP risk loci. In addition, they will also allow us to examine whether it is required to include all of the loci in the risk analyses or whether the analyses should include only those loci associated with the strongest risk estimates.

Another controversy limiting the implementation of these genetic loci into routine clinical practice is their association with disease aggressiveness. While some research groups have reported that aggressive forms of CaP are influenced by the same genetic variants associated with susceptibility, others have noted conflicting results. Our research group previously demonstrated that specific genetic variants are overrepresented in patients with adverse clinical features4-6. In particular, men who are carriers of variants along 8q24 and 17q12 are more likely to have high grade (i.e., Gleason score ≥7) disease. Other groups have also described similar findings between the genetic variants and the presence of aggressive features7-10. In the present study, we evaluated 4 of the 9 variants and found a trend towards higher grade disease and positive surgical margins in carriers of variants along 2p15 and 11q13, respectively. Further studies involving larger populations of men who underwent radical prostatectomy and have detailed available pathologic information are necessary to more completely elucidate the relationship between these variants and aggressive features.

Data derived from linkage analyses and GWAS have now confirmed the fact that no single gene locus mapped to date is by itself responsible for a large portion of CaP risk. Thus, identification of low-penetrance polymorphisms is integral to our understanding CaP genetics and susceptibility. In the future these CaP loci may be useful to help identify men at greatest risk for developing CaP. In addition, refining our understanding of their association with aggressive pathologic features could potentially enhance our ability to predict which patients have life threatening disease. Ultimately, these risk variants will translate into better diagnostic or more targeted therapeutic strategies for men with CaP.

References:

1. Bruner, D. W., Moore, D., Parlanti, A. et al.: Relative risk of prostate cancer for men with affected relatives: systematic review and meta-analysis. Int J Cancer, 107: 797, 2003

2. Zheng, S. L., Sun, J., Wiklund, F. et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med, 358: 910, 2008

3. Helfand, B. T., Fought, A. J., Loeb, S. et al.: Genetic prostate cancer risk assessment: common variants in 9 genomic regions are associated with cumulative risk. J Urol, 184: 501

4. Helfand, B. T., Loeb, S., Meeks, J. J.et al.: Pathological outcomes associated with the 17q prostate cancer risk variants. J Urol, 181: 2502, 2009

5. Helfand, B. T., Loeb, S., Kan, D. et al.: Prostate cancer genetic variants can assist in the identification of possibly "insigificant" disease. BJU Int, Accepted 2010

6. Helfand, B. T., Loeb, S., Cashy, J. et al.: Tumor characteristics of carriers and noncarriers of the deCODE 8q24 prostate cancer susceptibility alleles. J Urol, 179: 2197, 2008

7. Pal, P., Xi, H., Guha, S. et al.: Common variants in 8q24 are associated with risk for prostate cancer and tumor aggressiveness in men of European ancestry. Prostate, 2009

8. Gudmundsson, J., Sulem, P., Steinthorsdottir, V. et al.: Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat Genet, 39: 977, 2007

9. Freedman, M. L., Haiman, C. A., Patterson, N. et al.: Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American men. Proc Natl Acad Sci U S A, 103: 14068, 2006

10. Amundadottir, L. T., Sulem, P., Gudmundsson, J. et al.: A common variant associated with prostate cancer in European and African populations. Nat Genet, 38: 652, 2006

Written by Brian T. Helfand, MD and William J. Catalona, MD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations, etc., of their research by referencing the published abstract.

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Genetic Prostate Cancer Risk Assessment: Common Variants In 9 Genomic Regions Are Associated With Cumulative Risk