Faculty Bibliography

BACKGROUND: Epidemiologic studies have shown that men with type II diabetes have a lower risk of prostate cancer than non-diabetic men. Recently, common variants in two genes, HNF1B and JAZF1, were found to be associated with both of these diseases. METHODS: We examined whether the relationship between HNF1B and JAZF1 variants and decreased prostate cancer risk may potentially be mediated through diabetes in two large prospective studies, the Cancer Prevention Study II Nutrition Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. RESULTS: Three HNF1B SNPS, rs11649743, rs4430796, and rs7501939, were associated with decreased risk of prostate cancer and were also associated, with marginal statistical significance, with increased risk of diabetes. The JAZF1 SNPs rs6968704 and rs10486567 were associated with decreased risk of prostate cancer but were not associated with diabetes. All five SNP-prostate cancer relationships did not substantially differ when the analyses were stratified by diabetic status or when diabetic status was controlled for in the model. Furthermore, the association of diabetes with prostate cancer was not altered when the SNPs were included in the logistic model. CONCLUSIONS: These findings indicate that the HNF1B variants are directly associated with both diabetes and prostate cancer, that diabetes does not mediate these gene variant-prostate cancer relationships, and the relationship between these diseases is not mediated through these gene variants. Prostate (c) 2009 Wiley-Liss, Inc

Single nucleotide polymorphisms (SNPs) in the KLK3 gene on chromosome 19q13.33 are associated with serum prostate-specific antigen (PSA) levels. Recent genome wide association studies of prostate cancer have yielded conflicting results for association of the same SNPs with prostate cancer risk. Since the KLK3 gene encodes the PSA protein that forms the basis for a widely used screening test for prostate cancer, it is critical to fully characterize genetic variation in this region and assess its relationship with the risk of prostate cancer. We have conducted a next-generation sequence analysis in 78 individuals of European ancestry to characterize common (minor allele frequency, MAF >1%) genetic variation in a 56 kb region on chromosome 19q13.33 centered on the KLK3 gene (chr19:56,019,829-56,076,043 bps). We identified 555 polymorphic loci in the process including 116 novel SNPs and 182 novel insertion/deletion polymorphisms (indels). Based on tagging analysis, 144 loci are necessary to tag the region at an r (2) threshold of 0.8 and MAF of 1% or higher, while 86 loci are required to tag the region at an r (2) threshold of 0.8 and MAF >5%. Our sequence data augments coverage by 35 and 78% as compared to variants in dbSNP and HapMap, respectively. We observed six non-synonymous amino acid or frame shift changes in the KLK3 gene and three changes in each of the neighboring genes, KLK15 and KLK2. Our study has generated a detailed map of common genetic variation in the genomic region surrounding the KLK3 gene, which should be useful for fine-mapping the association signal as well as determining the contribution of this locus to prostate cancer risk and/or regulation of PSA expression

BACKGROUND:: The relation of physical activity across the lifespan to risk of prostate cancer has not been thoroughly investigated, particularly among black men. The authors investigated physical activity, including activity during different age periods and of various intensities, in relation to prostate cancer incidence among white men and black men. METHODS:: In total, 160,006 white men and 3671 black men ages 51 years to 72 years who were enrolled in the National Institutes of Health-AARP Diet and Health Study reported their time spent per week engaging in physical activity during ages 15 to 18 years, 19 years to 29 years, 35 years to 39 years, and during the past 10 years. Cox regression models were used to examine physical activity, categorized by intensity (moderate or vigorous, light, and total), in relation to prostate cancer risk. RESULTS:: During 7 years of follow-up, 9624 white men and 371 black men developed prostate cancer. Among white men, physical activity had no association with prostate cancer regardless of age period or activity intensity. Among black men, engaging in >/=4 hours of moderate/vigorous intensity physical activity versus infrequent activity during ages 19 years to 29 years was related to a 35% lower risk of prostate cancer (relative risk, 0.65; 95% confidence interval [95% CI], 0.43-0.99 [P(trend) = .01]). Frequent moderate/vigorous physical activity at ages 35 years to 39 years also potentially was related to reduced prostate cancer risk (relative risk, 0.59; 95% CI, 0.36-0.96 [P(trend) = .15]). CONCLUSIONS:: Regular physical activity may reduce prostate cancer risk among black men, and activity during young adulthood may yield the greatest benefit. This novel finding needs confirmation in additional studies. Cancer 2009. Published 2009 by the American Cancer Society

BACKGROUND: Circulating total cholesterol has been inversely associated with cancer risk; however, the role of reverse causation and the associations for high-density lipoprotein (HDL) cholesterol have not been fully characterized. We examined the relationship between serum total and HDL cholesterol and risk of overall and site-specific cancers among 29,093 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. METHODS: Fasting serum total and HDL cholesterol were assayed at baseline, and 7,545 incident cancers were identified during up to 18 years of follow-up. Multivariable proportional hazards models were conducted to estimate relative risks (RR). RESULTS: Higher serum total cholesterol concentration was associated with decreased risk of cancer overall (RR for comparing high versus low quintile, 0.85; 95% confidence interval, 0.79-0.91; P trend <0.001; >276.7 versus <203.9 mg/dL), and the inverse association was particularly evident for cancers of the lung and liver. These associations were no longer significant, however, when cases diagnosed during the first 9 years of follow-up were excluded. Greater HDL cholesterol was also associated with decreased risk of cancer (RR for high versus low quintile, 0.89; 95% confidence interval, 0.83-0.97; P trend = 0.01; >55.3 versus <36.2 mg/dL). The inverse association of HDL cholesterol was evident for cancers of lung, prostate, liver, and the hematopoietic system, and the associations of HDL cholesterol with liver and lung cancers remained after excluding cases diagnosed within 12 years of study entry. CONCLUSION: Our findings suggest that prior observations regarding serum total cholesterol and cancer are largely explained by reverse causation. Although chance and reverse causation may explain some of the inverse HDL associations, we cannot rule out some etiologic role for this lipid fraction.

Twin studies suggest a heritable component to circulating sex steroid hormones and sex hormone-binding globulin (SHBG). In the NCI-Breast and Prostate Cancer Cohort Consortium, 874 SNPs in 37 candidate genes in the sex steroid hormone pathway were examined in relation to circulating levels of SHBG (N=4,720), testosterone (N=4,678), 3alpha-androstanediol-glucuronide (N=4,767), and 17beta-estradiol (N=2,014) in Caucasian men. rs1799941 in SHBG is highly significantly associated with circulating levels of SHBG (p=4.52x10(-21)), consistent with previous studies, and testosterone (p=7.54x10(-15)), with mean difference of 26.9% and 14.3% respectively, comparing wildtype to homozygous variant carriers. Further noteworthy novel findings were observed between SNPs in ESR1 with testosterone levels (rs722208, mean difference=8.8%, p=7.37x10(-6)) and SRD5A2 with 3alpha-androstanediol-glucuronide (rs2208532, mean difference=11.8%, p=1.82x10(-6)). Genetic variation in genes in the sex steroid hormone pathway is associated with differences in circulating SHBG and sex steroid hormones

Background:The relationship between prostate cancer and height is uncertain.Methods:We prospectively examined the association of height with prostate cancer among 34268 men in the prostate, lung, colorectal, and ovarian cancer trial. Anthropometry was assessed at baseline and 2144 incident prostate cancer cases were identified upto 8.9 years of follow-up.Results:Overall, tallness was not associated with the risk of prostate cancer or with the risk of non-aggressive disease, but the risk for aggressive prostate cancer tended to be greater in taller men (Gleason score >/=7 or stage >/=III; P trend=0.05; relative risk (RR) for 190 cm+ vs </=170 cm=1.39, 95% confidence interval (95% CI): 0.96-2.01). This association was largely limited to men below the age of 65 years (P trend=0.008; RR for 190 cm+ vs </=170 cm=1.76, 95% CI: 1.06-2.93; P for interaction=0.009), although the number of cases was small and risk estimates were somewhat unstable.Conclusion:The results of this large prospective prostate cancer screening trial suggest that tallness is associated with increased risk for younger onset aggressive prostate cancer.British Journal of Cancer advance online publication, 30 June 2009; doi:10.1038/sj.bjc.6605159 www.bjcancer.com

Dietary antioxidants may interact with endogenous sources of pro- and antioxidants to impact breast cancer risk. A nested case-control study of postmenopausal women (505 cases and 502 controls) from the Cancer Prevention Study-II Nutrition Cohort was conducted to examine the interaction between oxidative stress-related genes and level of vegetable and fruit intake on breast cancer risk. Genetic variations in catalase (CAT) (C-262T), myeloperoxidase (MPO) (G-463A), endothelial nitric oxide synthase (NOS3) (G894T) and heme oxygenase-1 (HO-1) [(GT)(n) dinucleotide length polymorphism] were not associated with breast cancer risk. Women carrying the low-risk CAT CC [odds ratio (OR) = 0.75, 95% confidence interval (CI) 0.50-1.11], NOS3 TT (OR = 0.54, 95% CI = 0.26-1.12, P-trend = 0.10) or HO-1 S allele and MM genotype (OR = 0.56, 95% CI = 0.37-0.55), however, were found to be at non-significantly reduced breast cancer risk among those with high vegetable and fruit intake (> or = median; P-interactions = 0.04 for CAT, P = 0.005 for NOS3 and P = 0.07 for HO-1). Furthermore, those with > or = 4 putative low-risk alleles in total had significantly reduced risk (OR = 0.53, 95% CI = 0.32-0.88, P-interaction = 0.006) compared with those with < or = 2 low-risk alleles. In contrast, among women with low vegetable and fruit intake (< median), the low-risk CAT CC (OR = 1.33, 95% CI = 0.89-1.99), NOS3 TT (OR = 2.93, 95% CI = 1.38-6.22) and MPO AA (OR = 2.09, 95% CI = 0.73-5.95) genotypes appeared to be associated with raised breast cancer risk, with significantly increased risks observed in those with > or = 4 low-risk alleles compared with participants with < or = 2 low-risk alleles (OR = 1.77, 95% CI = 1.05-2.99, P-interaction = 0.006). Our results support the hypothesis that there are joint effects of endogenous and exogenous antioxidants