Cumulative Association Of Five Genetic Variants With Prostate Cancer

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Men's health;  Genetics
Article Date: 25 Feb 2008 - 0:00 PDT

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UroToday.com - In addition to age, race, and a positive family history it is now known that variants in chromosomal regions are associated with a risk of prostate cancer (CaP). These variants occur in three independent regions at 8q24 and in one region at 17q12 and another at 17q24.3. In the online version of the New England Journal of Medicine, Dr. Zheng and associates report a cumulative effect of these variants and the risk of CaP.

While the individual single-nucleotide polymorphisms (SNPs) in each of the chromosomal regions are moderately associated with risk of CaP, this study assessed the joint association. To do this, 2,893 subjects with CaP and 1781 controls had DNA extracted from blood samples and serum PSA levels measured. For CaP subjects, clinical and pathologic data were also recorded. A history of CaP among first-degree relatives was obtained from a questionnaire for both subjects and controls. The researchers selected 16 SNPs from the above cited chromosome regions and PCR reactions using extension primers were performed. The tests were performed in duplicate. Differences in allele frequencies between cases and controls were tested for each SNP and allelic odds ratios and 95% confidence intervals were estimated. The independent effect of each of the 5 implicated regions including the most significant SNP from each of the 5 regions was tested in a logistic-regression model. The odds ratio for CaP for men carrying any combination of 1, 2, 3, 4 or more genotypes associated with CaP was estimated by comparison with men carrying none of the CaP-associated genotypes. Population attributable risk (PAR) was estimated for SNPs that remained significant after adjustment for other covariates.

Significantly different frequencies between case and control subjects were observed for SNPs in each of the 5 chromosomal regions. The most significant SNP from each region in the individual analysis was selected to represent the region for analysis. These 5 SNPs remained significant after adjustment for the other SNPs and family history in multivariate analysis. The estimated joint PAR for CaP of the 5 associated SNPs plus family history was 46% in the studied population. The 5 SNPs had a cumulative association with CaP, after adjustment for age, geographic region, and family history. Men who carried 1, 2, 3, 4 or more of the 5 SNPs had an increasing likelihood of having CaP compared with men who did not carry any of the 5 SNPs. Family history was then included with the 5 SNPs (for a total possible score of 6) and men who carried any 5 or more of these 6 factors had an odds ratio of 9.46 for CaP as compared with men who carried none of the 6 factors. None of the 5 SNPs were significantly associated with the aggressiveness of CaP.

Zheng SL, Sun J, Wiklund F, Smith S, Stattin P, Li G, Adami HO, Hsu FC, Zhu Y, Bälter K, Kader AK, Turner AR, Liu W, Bleecker ER, Meyers DA, Duggan D, Carpten JD, Chang BL, Isaacs WB, Xu J, Grönberg H

N Engl J Med 2008:358 epub
doi: 10.1056/NEJMoa075819

Reported by UroToday.com Contributing Editor Christopher P. Evans, MD, FACS Professor & Chairman Department of Urology University of California, Davis, School of Medicine Sacramento, CA

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