Jong Y. Park

Deletion Polymorphism of UDP-Glucuronosyltransferase 2B17 and Risk of Prostate Cancer in African American and Caucasian Men

Purpose: UDP-glucuronosyltransferases (UGT) are a family of enzymes that glucuronidate many endogenous chemicals, including androgens. This makes them more hydrophilic, alters biological activity, and facilitates their excretion. A deletion polymorphism in the UGT2B17 gene was recently described that was associated with a reduced rate of glucuronidation in vivo. The purpose of this study was to determine if the deletion polymorphism is associated with susceptibility to prostate cancer. Materials and Methods: UGT2B17 expression was determined by reverse transcription-PCR of pathologically normal prostate tissues (n = 5). In a case-control study with 420 patients with incident primary prostate cancer (127 African Americans and 293 Caucasians) and 487 controls (120 African Americans and 367 Caucasians), the frequency of UGT2B17 deletion polymorphism in genomic DNA was compared between cases and controls with PCR analysis. Results: UGT2B17 mRNA was detected only in individuals with at least one UGT2B17 allele. The frequency of the null genotype was present in 0.11 and 0.12 of Caucasian and African American controls, respectively. When all subjects were considered, a significant association was found between the UGT2B17 deletion polymorphism and prostate cancer risk [odds ratio (OR), 1.7; 95% confidence interval (95% CI), 1.2-2.6]. There was an increase in prostate cancer risk among individuals with UGT2B17 deletion polymorphism in Caucasians (OR, 1.9; 95% CI, 1.2-3.0) but not in African Americans (OR, 1.3; 95% CI, 0.6-2.7). Conclusions: These results suggest that the UGT2B17 enzyme may play a role in the metabolism of androgens in prostate tissue and that the UGT2B17 deletion polymorphism is associated with prostate cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1473–8)

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease.

Validation of Genome-Wide Prostate Cancer Associations in Men of African Descent

Background: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent. Methods: We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci. Results: We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2. Conclusion: We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations. Impact: The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent. Cancer Epidemiol Biomarkers Prev; 20(1); 23–32. ©2011 AACR.

Association between polymorphisms in the DNA repair genes XRCC1 and APE1, and the risk of prostate cancer in white and black Americans.

PURPOSEnXRCC1 and APE1 are enzymes involved in the repair of DNA strand breaks and base damage that arise from various endogenous and exogenous oxidants. We determined whether polymorphisms in XRCC1 and APE1 increase the risk of prostate cancer.nnnMATERIALS AND METHODSnWe performed a case-control study in 228 white American men, 124 black American men, and 335 age, sex and race matched controls. Polymorphisms at codon 399 in XRCC1, and at codons 51 and 148 in APE1 were determined using an restriction fragment length polymorphism method. Frequencies were compared between cases and controls.nnnRESULTSnA significantly increased risk of prostate cancer was observed in white men with the XRCC1(399Gln) allele (OR 1.6, 95% CI 1.1 to 2.4). When APE1 and XRCC1 polymorphisms were evaluated together, we found an increased risk of the XRCC1(399Arg/Gln+Gln/Gln)/APE1(51Gln/Gln) (OR 4.0, 95% CI 1.3 to 12.5) and XRCC1(399Arg/Gln+Gln/Gln)/APE1(148Asp/Asp) (OR 2.9, 95% CI 1.4 to 6.1) genotypes in white men. Significant associations were found between combined genotypes and prostate cancer risk with a dose-effect relationship in white men (trend test p = 0.035 and 0.039, respectively). No significant associations were observed between polymorphisms in these genes and prostate cancer risk in black men.nnnCONCLUSIONSnOur results suggest that inherited variability in DNA repair capacity, as reflected by polymorphisms in XRCC1 and APE1, is a risk factor for prostate cancer.

Telomere length and risk of melanoma, squamous cell carcinoma, and basal cell carcinoma.

BACKGROUNDnTelomeres help maintain chromosomal structure and may influence tumorigenesis. We examined the association between telomere length and skin cancer in a clinic-based case-control study of 198 melanoma cases, 136 squamous cell carcinoma (SCC) cases, 185 basal cell carcinoma (BCC) cases, and 372 healthy controls.nnnMETHODSnCases were histologically confirmed patients treated at the Moffitt Cancer Center and University of South Florida Dermatology Clinic in Tampa, FL. Controls self-reported no history of cancer and underwent a skin cancer screening exam at study enrollment to rule out the presence of skin cancer. Quantitative real time PCR was used to measure telomere length in peripheral blood samples.nnnRESULTSnMelanoma patients had longer telomeres than controls (odds ratio (OR)=3.75; 95% confidence interval (CI): 2.02-6.94 for highest versus lowest tertile) (P for trend=<0.0001). In contrast, longer telomere length was significantly inversely associated with SCC (OR=0.01; 95% CI: 0.00-0.05 for highest versus lowest tertile) (P for trend=<0.0001) and BCC (OR=0.10; 95% CI: 0.06-0.19 for highest versus lowest tertile) (P for trend=<0.0001).nnnCONCLUSIONnTelomere length may be involved in the development of skin cancer, although the effect on cancer risk differs for melanoma and non-melanoma carcinomas. Our findings suggest that long telomere length is positively associated with melanoma while inversely associated with SCC and BCC.

The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium

BackgroundEpidemiological studies suggest a potential role for obesity and determinants of adult stature in prostate cancer risk and mortality, but the relationships described in the literature are complex. To address uncertainty over the causal nature of previous observational findings, we investigated associations of height- and adiposity-related genetic variants with prostate cancer risk and mortality.MethodsWe conducted a case–control study based on 20,848 prostate cancers and 20,214 controls of European ancestry from 22 studies in the PRACTICAL consortium. We constructed genetic risk scores that summed each man’s number of height and BMI increasing alleles across multiple single nucleotide polymorphisms robustly associated with each phenotype from published genome-wide association studies.ResultsThe genetic risk scores explained 6.31 and 1.46xa0% of the variability in height and BMI, respectively. There was only weak evidence that genetic variants previously associated with increased BMI were associated with a lower prostate cancer risk (odds ratio per standard deviation increase in BMI genetic score 0.98; 95xa0% CI 0.96, 1.00; pxa0=xa00.07). Genetic variants associated with increased height were not associated with prostate cancer incidence (OR 0.99; 95xa0% CI 0.97, 1.01; pxa0=xa00.23), but were associated with an increase (OR 1.13; 95 % CI 1.08, 1.20) in prostate cancer mortality among low-grade disease (p heterogeneity, low vs. high grade <0.001). Genetic variants associated with increased BMI were associated with an increase (OR 1.08; 95 % CI 1.03, 1.14) in all-cause mortality among men with low-grade disease (p heterogeneityxa0=xa00.03).ConclusionsWe found little evidence of a substantial effect of genetically elevated height or BMI on prostate cancer risk, suggesting that previously reported observational associations may reflect common environmental determinants of height or BMI and prostate cancer risk. Genetically elevated height and BMI were associated with increased mortality (prostate cancer-specific and all-cause, respectively) in men with low-grade disease, a potentially informative but novel finding that requires replication.

Prostate Cancer Predisposition Loci and Risk of Metastatic Disease and Prostate Cancer Recurrence

Purpose: Genome-wide association studies (GWAS) have identified multiple novel prostate cancer predisposition loci. Whether these common genetic variants are associated with incident metastatic prostate cancer or with recurrence after surgical treatment for clinically localized prostate cancer is uncertain. Experimental Design: Twelve single nucleotide polymorphisms (SNPs) were selected for study in relation to prostate metastatic cancer and recurrence, based on their genome-wide association with prostate cancer in the Cancer Genetic Markers of Susceptibility (CGEMS). To assess risk for metastatic disease, we compared genotypes for the 12 SNPs by logistic regression of 470 incident metastatic prostate cancer cases and 1,945 controls in 3 case-control studies. To assess the relationship of these SNPs to risk for prostate cancer recurrence, we used Cox regression in a cohort of 1,412 men treated for localized prostate cancer, including 328 recurrences, and used logistic regression in a case-case study, comparing 450 recurrent versus 450 nonrecurrent prostate cancer cases. Study-specific relative risks (RRs) for risk of metastatic disease and recurrence were summarized using meta-analysis, with inverse variance weights. Results: MSMB rs10993994 (per variant allele summary RR = 1.24, 95% CI = 1.05–1.48), 8q24 rs4242382 (RR = 1.40, 95% CI = 1.13–1.75), and 8q24 rs6983267 (RR = 0.67, 95% CI = 0.50–0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with prostate cancer recurrence. Conclusions: SNPs in MSMB and 8q24 which predispose to prostate cancer overall are associated with risk for metastatic prostate cancer, the most lethal form of this disease. SNPs predictive of prostate cancer recurrence were not identified, among the predisposition SNPs. GWAS specific to these 2 phenotypes may identify additional phenotype-specific genetic determinants. Clin Cancer Res; 17(5); 1075–81. ©2011 AACR.

Telomere length in myelodysplastic syndromes

The relationship between telomere length (TL) and predisposition to myelodysplastic syndromes (MDS) remains unclear. We compared peripheral blood leukocyte (PBL) TL among cases of histologically confirmed MDS (nu200a=u200a65) who were treatment-naive with no prior cancer history to age-matched controls (nu200a=u200a63). Relative TL was measured in PBLs and saliva by quantitative polymerase chain reaction (PCR) and in CD15+ and CD19+ cells by flow cytometry-fluorescence in situ hybridization (flow-FISH). Human telomerase reverse transcriptase gene (hTERT) mutations were assessed by PCR. After adjustment for age and sex, relative TLs were reduced in PBLs (pu200a=u200a0.02), CD15+ (pu200a=u200a0.01), CD19+ (pu200a=u200a0.25), and saliva (pu200a=u200a0.13) in MDS cases versus controls, although only the PBL and CD15+ results were statistically significant. Among MDS cases, CD15+ and CD19+ cell TLs were positively correlated (pu200a=u200a0.03). PBL TL was reduced among those occupationally exposed to paints and pesticides, but was not associated with hTERT genotype. Future studies are needed to further investigate constitutional telomere attrition as a possible predisposing factor for MDS.

Generalizability of established prostate cancer risk variants in men of African ancestry

Genome‐wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at pu2009<u20090.05, with the most statistically significant variants being rs116041037 (pu2009=u20093.7 × 10−26) and rs6983561 (pu2009=u20091.1 × 10−16) at 8q24, as well as rs7210100 (pu2009=u20095.4 × 10−8) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (pu2009<u20090.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per‐allele odds ratio (OR)u2009=u20091.12, pu2009=u20097.3 × 10−98]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Fine-Mapping the HOXB Region Detects Common Variants Tagging a Rare Coding Allele: Evidence for Synthetic Association in Prostate Cancer

The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, Pu200a=u200a2.62×10−14). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.