| 1. |
- Bailey-Wilson, Joan E, et al.
(författare)
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Analysis of Xq27-28 linkage in the international consortium for prostate cancer genetics (ICPCG) families
- 2012
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Ingår i: BMC Medical Genetics. - London : BioMed Central. - 1471-2350. ; 13, s. 46-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genetic variants are likely to contribute to a portion of prostate cancer risk. Full elucidation of the genetic etiology of prostate cancer is difficult because of incomplete penetrance and genetic and phenotypic heterogeneity. Current evidence suggests that genetic linkage to prostate cancer has been found on several chromosomes including the X; however, identification of causative genes has been elusive.Methods: Parametric and non-parametric linkage analyses were performed using 26 microsatellite markers in each of 11 groups of multiple-case prostate cancer families from the International Consortium for Prostate Cancer Genetics (ICPCG). Meta-analyses of the resultant family-specific linkage statistics across the entire 1,323 families and in several predefined subsets were then performed.Results: Meta-analyses of linkage statistics resulted in a maximum parametric heterogeneity lod score (HLOD) of 1.28, and an allele-sharing lod score (LOD) of 2.0 in favor of linkage to Xq27-q28 at 138 cM. In subset analyses, families with average age at onset less than 65 years exhibited a maximum HLOD of 1.8 (at 138 cM) versus a maximum regional HLOD of only 0.32 in families with average age at onset of 65 years or older. Surprisingly, the subset of families with only 2-3 affected men and some evidence of male-to-male transmission of prostate cancer gave the strongest evidence of linkage to the region (HLOD = 3.24, 134 cM). For this subset, the HLOD was slightly increased (HLOD = 3.47 at 134 cM) when families used in the original published report of linkage to Xq27-28 were excluded.Conclusions: Although there was not strong support for linkage to the Xq27-28 region in the complete set of families, the subset of families with earlier age at onset exhibited more evidence of linkage than families with later onset of disease. A subset of families with 2-3 affected individuals and with some evidence of male to male disease transmission showed stronger linkage signals. Our results suggest that the genetic basis for prostate cancer in our families is much more complex than a single susceptibility locus on the X chromosome, and that future explorations of the Xq27-28 region should focus on the subset of families identified here with the strongest evidence of linkage to this region.
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| 2. |
- Christensen, G Bryce, et al.
(författare)
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Genome-wide linkage analysis of 1,233 prostate cancer pedigrees from the International Consortium for prostate cancer Genetics using novel sumLINK and sumLOD analyses.
- 2010
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 70, s. 735-744
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer (PC) is generally believed to have a strong inherited component, but the search for susceptibility genes has been hindered by the effects of genetic heterogeneity. The recently developed sumLINK and sumLOD statistics are powerful tools for linkage analysis in the presence of heterogeneity. METHODS: We performed a secondary analysis of 1,233 PC pedigrees from the International Consortium for Prostate Cancer Genetics (ICPCG) using two novel statistics, the sumLINK and sumLOD. For both statistics, dominant and recessive genetic models were considered. False discovery rate (FDR) analysis was conducted to assess the effects of multiple testing. RESULTS: Our analysis identified significant linkage evidence at chromosome 22q12, confirming previous findings by the initial conventional analyses of the same ICPCG data. Twelve other regions were identified with genome-wide suggestive evidence for linkage. Seven regions (1q23, 5q11, 5q35, 6p21, 8q12, 11q13, 20p11-q11) are near loci previously identified in the initial ICPCG pooled data analysis or the subset of aggressive PC pedigrees. Three other regions (1p12, 8p23, 19q13) confirm loci reported by others, and two (2p24, 6q27) are novel susceptibility loci. FDR testing indicates that over 70% of these results are likely true positive findings. Statistical recombinant mapping narrowed regions to an average of 9 cM. CONCLUSIONS: Our results represent genomic regions with the greatest consistency of positive linkage evidence across a very large collection of high-risk PC pedigrees using new statistical tests that deal powerfully with heterogeneity. These regions are excellent candidates for further study to identify PC predisposition genes. Prostate (c) 2010 Wiley-Liss, Inc.
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| 3. |
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| 4. |
- Hsu, Fang-Chi, et al.
(författare)
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A novel prostate cancer susceptibility locus at 19q13.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:7, s. 2720-3
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Tidskriftsartikel (refereegranskat)abstract
- A two-stage genome-wide association study (GWAS) of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative identified single nucleotide polymorphisms (SNP) in 150 regions across the genome that may be associated with prostate cancer (PCa) risk. We filtered these results to identify 43 independent SNPs where the frequency of the risk allele was consistently higher in cases than in controls in each of the five CGEMS study populations. Genotype information for 22 of these 43 SNPs was obtained either directly by genotyping or indirectly by imputation in our PCa GWAS of 500 cases and 500 controls selected from a population-based case-control study in Sweden [Cancer of the Prostate in Sweden (CAPS)]. Two of these 22 SNPs were significantly associated with PCa risk (P<0.05). We then genotyped these two SNPs in the remaining cases (n=2,393) and controls (n=1,222) from CAPS and found that rs887391 at 19q13 was highly associated with PCa risk (P=9.4 x 10(-4)). A similar trend of association was found for this SNP in a case-control study from Johns Hopkins Hospital (JHH), albeit the result was not statistically significant. Altogether, the frequency of the risk allele of rs887391 was consistently higher in cases than controls among each of seven study populations examined, with an overall P=3.2 x 10(-7) from a combined allelic test. A fine-mapping study in a 110-kb region at 19q13 among CAPS and JHH study populations revealed that rs887391 was the most strongly associated SNP in the region. Additional confirmation studies of this region are warranted.
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| 5. |
- Liu, Wennuan, et al.
(författare)
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Association of a germ-line copy number variation at 2p24.3 and risk for aggressive prostate cancer.
- 2009
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Ingår i: Cancer research. - 1538-7445. ; 69:6, s. 2176-9
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Tidskriftsartikel (refereegranskat)abstract
- We searched for deletions in the germ-line genome among 498 aggressive prostate cancer cases and 494 controls from a population-based study in Sweden [CAncer of the Prostate in Sweden (CAPS)] using Affymetrix SNP arrays. By comparing allele intensities of approximately 500,000 SNP probes across the genome, a germ-line deletion at 2p24.3 was observed to be significantly more common in cases (12.63%) than in controls (8.28%); P = 0.028. To confirm the association, we genotyped this germ-line copy number variation (CNV) in additional subjects from CAPS and from Johns Hopkins Hospital (JHH). Overall, among 4,314 cases and 2,176 controls examined, the CNV was significantly associated with prostate cancer risk [odds ratio (OR), 1.25; 95% confidence interval (95% CI), 1.06-1.48; P = 0.009]. More importantly, the association was stronger for aggressive prostate cancer (OR, 1.31; 95% CI, 1.08-1.58; P = 0.006) than for nonaggressive prostate cancer (OR, 1.19; 95% CI, 0.98-1.45; P = 0.08). The biological effect of this germ-line CNV is unknown because no known gene resides in the deletion. Results from this study represent the first novel germ-line CNV that was identified from a genome-wide search and was significantly, but moderately, associated with prostate cancer risk. Additional confirmation of this association and functional studies are warranted.
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| 6. |
- Wiklund, Fredrik, et al.
(författare)
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Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:4, s. 419-427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS. We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS. Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P <= 0.05) were found for six SNPs. These six SNP's had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS. Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening. Prostate 69: 419-427, 2009. (C) 2008 Wiley-Liss, Inc.
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| 7. |
- Zheng, S. Lilly, et al.
(författare)
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A comprehensive association study for genes in inflammation pathway provides support for their roles in prostate cancer risk in the CAPS study
- 2006
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Ingår i: The Prostate. - Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. Karolinska Inst, Dept Med Epidemiol & Biotat, Stockholm, Sweden. Orebro Univ Hosp, Dept Urol & Clin Med, Orebro, Sweden. Translat Genom Res Inst, Phoenix, AZ USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:14, s. 1556-1564
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Recently identified associations of prostate cancer risk with several genes involved in innate immunity support a role of inflammation in the etiology of prostate cancer. Considering inflammation is regulated by a complex system of gene products, we hypothesize sequence variants in many other genes of this pathway are associated with prostate cancer. METHODS. We evaluated 9,275 SNPs; in 1,086 genes of the inflammation pathway using a MegAlleleTM genotyping system among 200 familial cases and 200 unaffected controls selected from a large Swedish case-control population (CAPS). RESULTS. We found that significantly more than the expected numbers of SNPs were significant at a nominal P-value of 0.01, 0.05, and 0.1, providing overall support for our hypothesis. The excess was largest when using a more liberal nominal P-value (0.1); we observed 992 significant SNPs compared with the 854 significant SNPs expected by chance, and this difference was significant based on a permutation test (P = 0.0025). We also began the effort of differentiating true associated SNPs by selecting a small subset of significant SNPs (N = 26) and genotyped these in an independent sample of similar to 1,900 CAPS1 subjects. We were able to confirm 3 of these 26 SNPs. It is expected that many more true associated SNPs will be confirmed among the 992 significant SNPs identified in our pathway screen. CONCLUSIONS. Our study provides the first objective support for an association between prostate cancer and multiple modest-effect genes in inflammatory pathways.
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| 8. |
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| 9. |
- Zheng, S. Lilly, et al.
(författare)
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Genetic variants and family history predict prostate cancer similar to prostate-specific antigen
- 2009
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 15:3, s. 1105-1111
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Although prostate-specific antigen (PSA) is the best biomarker for predicting prostate cancer, its predictive performance needs to be improved. Results from the Prostate Cancer Prevention Trial revealed the overall performance measured by the areas under curve of the receiver operating characteristic at 0.68. The goal of the present study is to assess the ability of genetic variants as a PSA-independent method to predict prostate cancer risk. EXPERIMENTAL DESIGN: We systematically evaluated all prostate cancer risk variants that were identified from genome-wide association studies during the past year in a large population-based prostate cancer case-control study population in Sweden, including 2,893 prostate cancer patients and 1,781 men without prostate cancer. RESULTS: Twelve single nucleotide polymorphisms were independently associated with prostate cancer risk in this Swedish study population. Using a cutoff of any 11 risk alleles or family history, the sensitivity and specificity for predicting prostate cancer were 0.25 and 0.86, respectively. The overall predictive performance of prostate cancer using genetic variants, family history, and age, measured by areas under curve was 0.65 (95% confidence interval, 0.63-0.66), significantly improved over that of family history and age (0.61%; 95% confidence interval, 0.59-0.62; P = 2.3 x 10(-10)). CONCLUSION: The predictive performance for prostate cancer using genetic variants and family history is similar to that of PSA. The utility of genetic testing, alone and in combination with PSA levels, should be evaluated in large studies such as the European Randomized Study for Prostate Cancer trial and Prostate Cancer Prevention Trial.
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