Prostate Cancer: Single Nucleotide Polymorphisms and Prostate Cancer Susceptibility

News and Views from the Literature

9a. RIU0418_12-11.qxd 12/11/08 10:38 PM Page 304 REVIEWING THE LITERATURE News and Views from the Literature Prostate Cancer Single Nucleotide Polymorphisms and Prostate Cancer Susceptibility Reviewed by Stacy Loeb, MD, Alan W. Partin MD, PhD The James Buchanan Brady Urological Institute, Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD [Rev Urol. 2008;10(4):304-305] © 2008 MedReviews®, LLC ccording to twin studies, heritable factors account for a substantial fraction of prostate cancer risk.1 Until recently, linkage studies were primarily used to identify gene mutations that cosegregate in prostate cancer families. A notable example is the HPC1 gene on chromosome 1q24-25.2 Unfortunately, such gene mutations account for a small minority of familial prostate cancer cases, so investigation has continued for more prevalent genetic variants. The development of genome-wide association studies has facilitated the search for more common genetic variants. Indeed, numerous single nucleotide polymorphisms (SNPs) have recently been identified that might play an aggregate role in prostate cancer susceptibility. Two articles from the literature highlight these exciting new developments in the field of prostate cancer genetics. A 304 VOL. 10 NO. 4 2008 REVIEWS IN UROLOGY A Common Variant Associated With Prostate Cancer in European and African Populations Amundadottir LT, Sulem P, Gudmundsson J, et al. Nat Genet. 2006;38:652-658. n a landmark 2006 study, Amundadottir and colleagues reported that multiple SNPs located at chromosome 8q24 had a significant association with prostate cancer susceptibility. First, they identified a strong signal on 8q24, using a genome-wide linkage scan in Icelandic families with prostate cancer. They then genotyped 3 separate casecontrol populations of European or European American ancestry and reported a combined 1.62-fold increased odds ratio (OR) for the 8 allele of the microsatellite marker DG8S737. Another variant, the A allele at rs1447295, also demonstrated a significant association with prostate cancer susceptibility in these 3 case-control populations. Additional investigation in African men revealed a considerably higher prevalence of the 8q24 variants in this population. Although there was also an increased frequency of the 8 allele in African American prostate cancer cases compared with controls (23.4% vs 16.1%, OR 1.60; P  .0022), the association with allele A at rs1447295 was not statistically significant (P  .29). Finally, the authors examined the association between these susceptibility alleles and tumor grade. Combining prostate cancer cases from all 4 populations, they reported a significantly greater frequency of the 8 allele among affected individuals with high-grade (Gleason score 7-10) than lowergrade (Gleason score  6) disease (OR 1.21; P  .02). I 9a. RIU0418_12-11.qxd 12/17/08 10:51 AM Page 305 Prostate Cancer Several confirmatory studies have since validated the association between these 8q24 variants and prostate cancer susceptibility in multiple ethnic groups.3,4 Particularly important was the identification of this region by admixture mapping in African Americans.5 In addition, the same authors subsequently reported on 2 additional prostate cancer susceptibility variants, located on chromosome 17q12 and 17q24.3.6 These combined findings represent a major breakthrough in elucidating the genetic basis for prostate cancer. The results of Zheng and colleagues suggest that multiple SNPs may play a significant aggregate role in determining prostate cancer risk. Nevertheless, further study is necessary to examine whether any combination of genetic variants can be used to predict the probability of lifethreatening disease. References 1. 2. Cumulative Association of Five Genetic Variants With Prostate Cancer Zheng SL, Sun J, Wiklund F, et al. 3. 4. N Engl J Med. 2008;358:910-919. 5. ecently, Zheng and colleagues carried the association between SNPs and prostate cancer susceptibility to the next level. Specifically, in 2893 Swedish prostate cancer patients and 1781 healthy controls from the Swedish Population Registry, they examined loci from 3 different regions on chromosome 8q24 and 2 at chromosome 17q. As in prior studies, they found significant differences in allele frequency between cases and controls for all 5 alleles (P  .05). In addition, they used logistic regression analysis to evaluate for the cumulative effects of SNPs on 8q24, 17q12, and 17q24. In the multivariate model, all 5 SNPs remained significantly associated with prostate cancer susceptibility. Moreover, the risk of prostate cancer continuously increased for carriers of 1 versus 2, 3, 4, or more SNPs (P value for trend, 6.75  1027). Moreover, men with a positive family history and 5 or more alleles had 9.46-fold increased odds of prostate cancer, compared with men with none of the alleles (P value for trend, 9.78  1028). It is noteworthy that the cumulative effect of these SNPs on prostate cancer risk has since been validated in multiple study populations.7 Finally, the authors tested whether there was an association between these SNPs with advanced prostate cancer (defined as any of the following: stage 3 or 4, lymph node or distant metastases, Gleason score  8, or prostatespecific antigen level  50 ng/mL). Comparing cases with 4 or more alleles with noncarriers, they did not find any significant difference in the proportion with advanced disease (54% vs 48%; P  .33). Indeed, there is controversy in the literature regarding the relationship between these recently identified susceptibility alleles and prostate cancer aggressiveness. Some studies have failed to demonstrate any association, whereas others have reported a significantly greater risk of adverse pathologic tumor features in carriers of the 8 or multiple 8q24 alleles.8,9 R 6. 7. 8. 9. Lichtenstein P, Holm NV, Verkasalo PK, et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78-85. Smith JR, Freije D, Carpten JD, et al. Major susceptibility locus for prostate cancer on chromosome 1 suggested by a genome-wide search. Science. 1996;274: 1371-1374. Haiman CA, Patterson N, Freedman ML, et al. Multiple regions within 8q24 independently affect risk for prostate cancer. Nat Genet. 2007;39:638-644. Witte JS. Multiple prostate cancer risk variants on 8q24. Nat Genet. 2007;39: 579-580. Freedman ML, Haiman CA, 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. 2006;103:14068-14073. 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. 2007;39:977-983. Sun J, Chang BL, Isaacs SD, et al. Cumulative effect of five genetic variants on prostate cancer risk in multiple study populations. Prostate. 2008;68:1257-1262. Helfand BT, Loeb S, Cashy J, et al. Tumor characteristics of carriers and noncarriers of the deCODE 8q24 prostate cancer susceptibility alleles. J Urol. 2008;179:2197-2201; discussion 2202. Suuriniemi M, Agalliu I, Schaid DJ, et al. Confirmation of a positive association between prostate cancer risk and a locus at chromosome 8q24. Cancer Epidemiol Biomarkers Prev. 2007;16:809-814. Androgen Deprivation Therapy Reviewed by Paul Hoffman, MD, Bob Djavan, MD, PhD Department of Urology, University of Brussels, Brussels, Belgium [Rev Urol. 2008;10(4):305-306] © 2008 MedReviews®, LLC n the past decade, androgen deprivation therapy (ADT) has been increasingly used in earlier stages of prostate cancer, despite the presence of mature data from large-scale randomized trials suggesting no survival advantage from earlier intervention. ADT remains a palliative treatment with minimal effect on survival, with almost all patients dying from prostate cancer having hormone-refractory prostate cancer with castrate levels of testosterone. I Survival Following Primary Androgen Deprivation Therapy Among Men With Localized Prostate Cancer Lu-Yao GL, Albertsen PC, Moore DF, et al. JAMA. 2008;300:173-181. Despite unproven indications, increasing numbers of patients are receiving primary ADT (PADT) as an alternative VOL. 10 NO. 4 2008 REVIEWS IN UROLOGY 305