Faculty Bibliography

BACKGROUND: Research on the association between fruit and vegetable intake and risk of colorectal adenoma is inconclusive. OBJECTIVE: We studied whether intake of fruit, vegetables, or their subgroups is associated with a lower risk of prevalent colorectal adenoma. DESIGN: In men and women (aged 55-74 y) who were screened for colorectal cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) (1993-2001), we compared 3,057 cases with at least one prevalent histologically verified adenoma of the distal large bowel with 29,413 control subjects. Using a food-frequency questionnaire, we quantified intake of fruit and vegetables in the 12 mo before screening as energy-adjusted pyramid servings/d (ps/d). Adjusted odds ratios (ORs) and 95% CIs were estimated by logistic regression. RESULTS: Risk of distal adenoma was significantly lower among subjects in high (approximately 5.7 ps/d) versus low (approximately 1.2 ps/d) quintiles of total fruit intake (OR: 0.75; 95% CI: 0.66, 0.86, P for trend <0.001), which was not completely explained by dietary folate or fiber intake. Inverse associations between adenoma and total fruit intake were observed regardless of adenoma histopathology and multiplicity. However, the protective effect was seen only for colon and not rectal adenoma. Total vegetable intake was not significantly associated with reduced risk of adenoma. ORs for colorectal adenoma among persons with high versus low intakes of deep-yellow vegetables, dark-green vegetables, and onions and garlic were significantly related to lower risk of adenoma, although the P for trend for dark-green vegetables was not significant. CONCLUSION: Diets rich in fruit and deep-yellow vegetables, dark-green vegetables, and onions and garlic are modestly associated with reduced risk of colorectal adenoma, a precursor of colorectal cancer

CYP17 encodes cytochrome p450c17alpha, which mediates activities essential for the production of sex steroids. Common germ line variation in the CYP17 gene has been related to inconsistent results in breast and prostate cancer, with most studies focusing on the nonsynonymous single nucleotide polymorphism (SNP) T27C (rs743572). We comprehensively characterized variation in CYP17 by direct sequencing of exons followed by dense genotyping across the 58 kb region around CYP17 in five racial/ethnic populations. Two blocks of strong linkage disequilibrium were identified and nine haplotype-tagging SNPs, including T27C, were chosen to predict common haplotypes (R(h)(2) >or= 0.85). These haplotype-tagging SNPs were genotyped in 8,138 prostate cancer cases and 9,033 controls, and 5,333 breast cancer cases and 7,069 controls from the Breast and Prostate Cancer Cohort Consortium. We observed borderline significant associations with prostate cancer for rs2486758 [TC versus TT, odds ratios (OR), 1.07; 95% confidence intervals (95% CI), 1.00-1.14; CC versus TT, OR, 1.09; 95% CI, 0.95-1.26; P trend=0.04] and rs6892 (AG versus AA, OR, 1.08; 95% CI, 1.00-1.15; GG versus AA, OR, 1.11; 95% CI, 0.95-1.30; P trend=0.03). We also observed marginally significant associations with breast cancer for rs4919687 (GA versus GG, OR, 1.04; 95% CI, 0.97-1.12, AA versus GG, OR, 1.17; 95% CI, 1.03-1.34; P trend=0.03) and rs4919682 (CT versus CC, OR, 1.04; 95% CI, 0.97-1.12; TT versus CC, OR, 1.16; 95% CI, 1.01-1.33; P trend=0.04). Common variation at CYP17 was not associated with circulating sex steroid hormones in men or postmenopausal women. Our findings do not support the hypothesis that common germ line variation in CYP17 makes a substantial contribution to postmenopausal breast or prostate cancer susceptibility

The 2005 Dietary Guidelines for Americans include quantitative recommendations for 2 eating patterns, the USDA Food Guide and the Dietary Approaches to Stop Hypertension (DASH) Eating Plan, to promote optimal health and reduce disease risk. A Mediterranean dietary pattern has also been promoted for health benefits. Our objective was to determine whether adherence to the USDA Food Guide recommendations, the DASH Eating Plan, or a Mediterranean dietary pattern is associated with reduced risk of distal colorectal adenoma. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, men and women aged 55-74 y were screened for colorectal cancer by sigmoidoscopy at 10 centers in the U.S. After adjusting for potential confounders, men who most complied with the USDA Food Guide recommendations had a 26% reduced risk of colorectal adenoma compared with men who least complied with the recommendations (OR USDA score >or= 5 vs. <or=2 = 0.74, 95% CI = 0.64-0.85; P-trend < 0.001). Comparable results were found for men who had intakes most similar to the DASH Eating Plan or a Mediterranean dietary pattern. Women who most complied with the USDA Food Guide recommendations had an 18% reduced risk for colorectal adenoma, but subgroup analyses revealed protective associations only for current smokers (OR USDA score >or= 5 vs. <or=2 = 0.52, 95% CI = 0.31-0.89; P-trend < 0.01) or normal-weight women (OR USDA score >or= 5 vs. <or=2 = 0.74, 95% CI = 0.55-0.99; P-trend = 0.08). Following the current U.S. dietary recommendations or a Mediterranean dietary pattern is associated with reduced risk of colorectal adenoma, especially in men

BACKGROUND: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis. METHODS: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>or=T3b, N1, or M1) and high-grade (Gleason sum >or=8) prostate cancer, respectively. RESULTS: The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer. CONCLUSION: In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer

BACKGROUND: alpha-Methylacyl-CoA racemase (AMACR), an enzyme involved in oxidation of branched chain fatty acids and cholesterol metabolites, as well as ibuprofen metabolism, is overexpressed in colorectal adenomas and cancer. AMACR gene variants have been associated with hereditary prostate cancer, but no studies have evaluated their etiologic role in colorectal carcinogenesis. METHODS: We conducted a case-control study of 725 advanced distal colorectal adenoma cases and 729 frequency-matched controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Seven AMACR polymorphisms were genotyped. Unconditional logistic regression models were used to evaluate the associations adjusting for age at randomization and gender. RESULTS: The 201L allele of S201L [TT versus CC: odds ratio (OR), 1.74; 95% confidence interval (95% CI), 1.15-2.62; TC versus CC: OR, 1.17; 95% CI, 0.93-1.49] and the 277E allele of K277E (GG versus AA: OR, 1.66; 95% CI, 1.03-2.68; GA versus AA: OR, 1.21; 95% CI, 0.96-1.53) were associated with increased risk of advanced distal colorectal adenoma (both P(trend) </= 0.02); the TGTGCG haplotype of six informative single nucleotide polymorphisms was also associated with increased risk (OR, 1.27; 95% CI, 1.03-1.55). Regular ibuprofen users who were homozygous for the variant allele at either M9V or D175G were at reduced risk for adenoma (both P(interaction) < 0.05). CONCLUSION: Our study identified variants in AMACR associated with advanced distal colorectal adenoma and pointed to potential interactions with ibuprofen use

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR), which prepares branched chain fatty acids to be metabolized for energy and is implicated in the activation of the COX-inhibiting form of ibuprofen, is overexpressed in prostate cancer and its precursor lesions. Significant differences in AMACR allele frequencies have been reported for hereditary prostate cancer (HPC), but the relevance of AMACR in the context of its substrates have not been studied. METHODS: We conducted a nested case-control study of 1,318 prostate cancer cases and 1,842 controls from the screening arm of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Five non-synonymous (nsSNP) and two intronic AMACR polymorphisms were genotyped. Conditional logistic regression models were used to evaluate the associations between the genetic variants and prostate cancer. RESULTS: Overall, prostate cancer was not related to AMACR gene variants; however, risks for prostate cancer were significantly reduced among regular ibuprofen users who carried allele variants at four nsSNP loci (M9V, D175G, S201L, and K277E; all P(trend) < 0.05) or carried the TGTGCG haplotype (OR = 0.65; 95% CI 0.44-0.97). No AMACR-related associations were noted among nonregular ibuprofen users (all P(interaction) > 0.33). CONCLUSION: AMACR gene variants were unrelated to prostate cancer overall in this study. The protective associations observed among ibuprofen users suggest that AMACR gene variants may enhance the chemopreventive effects of ibuprofen on prostate cancer risk

BACKGROUND: Several epidemiologic studies have reported associations between fruit and vegetable intake and reduced risk of prostate cancer, but the findings are inconsistent and data on clinically relevant advanced prostate cancer are limited. METHODS: We evaluated the association between prostate cancer risk and intake of fruits and vegetables in 1338 patients with prostate cancer among 29,361 men (average follow-up = 4.2 years) in the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Participants completed both a general risk factor and a 137-item food-frequency questionnaire at baseline. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. RESULTS: Vegetable and fruit consumption was not related to prostate cancer risk overall; however, risk of extraprostatic prostate cancer (stage III or IV tumors) decreased with increasing vegetable intake (RR = 0.41, 95% CI = 0.22 to 0.74, for high versus low intake; P(trend) = .01). This association was mainly explained by intake of cruciferous vegetables (RR = 0.60, 95% CI = 0.36 to 0.98, for high versus low intake; P(trend) = .02), in particular, broccoli (RR = 0.55, 95% CI = 0.34 to 0.89, for >1 serving per week versus <1 serving per month; P(trend) = .02) and cauliflower (RR = 0.48, 95% CI = 0.25 to 0.89 for >1 serving per week versus <1 serving per month; P(trend) = .03). We found some evidence that risk of aggressive prostate cancer decreased with increasing spinach consumption, but the findings were not consistently statistically significant when restricted to extraprostatic disease. CONCLUSION: High intake of cruciferous vegetables, including broccoli and cauliflower, may be associated with reduced risk of aggressive prostate cancer, particularly extraprostatic disease

Superoxide dismutase (SOD) plays a key role in the detoxification of superoxide free radicals. We evaluated the association of prostate cancer with genetic polymorphisms in SOD1 (CuZn-SOD; IVS3-251A>G), SOD2 [MnSOD; Ex2+24T>C (V16A)], and SOD3 (EC-SOD; IVS1+186C>T, Ex3-631C>G, Ex3-516C>T, and Ex3-489C>T), the three main isoforms of SOD. Prostate cancer cases (n = 1,320) from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were frequency matched to nondiseased controls (n = 1,842) by age, race, time since initial screening, and year of blood draw. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI); stratified analysis by the level of antioxidative vitamins was also conducted. The higher activity Ala variant at SOD2 Ex2+24T>C (V16A), which has been hypothesized to suppress prostate carcinogenesis, was associated with elevation of prostate cancer risk in Caucasians (Val/Ala versus Val/Val: OR, 1.17; 95% CI, 0.97-1.42; Ala/Ala versus Val/Val: OR, 1.28; 95% CI, 1.03-1.60; P(trend) = 0.03). Stratification by quartiles of dietary and supplemental vitamin E intake (IU/d) showed risks of prostate cancer tended to be increased among SOD2 Ala allele carriers, except at the highest quartile of vitamin E intake (>222; P(interaction) = 0.06, Q1-Q3 versus Q4). The association between Ala allele and prostate cancer risk among those with lower intake of vitamin E (</=222) was stronger for smokers (OR, 1.44; 95% CI, 1.10-1.90). No significant association with prostate cancer was observed for polymorphic variants in SOD3 or SOD1. These results suggest that the Ala variant of SOD2 is associated with moderately increased risk of prostate cancer, particularly among men with lower intakes of dietary and supplemental vitamin E

Transforming growth factor beta 1 (TGFB1) is a multifunctional cytokine that has been implicated in the pathogenesis of colorectal neoplasia. To investigate the association between genetic variants in TGFB1 and the risk of colorectal adenoma, we conducted a case-control study of 754 advanced adenoma cases and 769 controls from the baseline screening exam of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma (>or=1 cm, high-grade dysplasia or villous characteristics), and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy. DNA was extracted from blood specimens, and five single-nucleotide polymorphisms in TGFB1 of known or suggested functional significance (-800G>A, -509C>T, Leu10Pro, Arg25Pro and Thr263Ile) were genotyped. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for the association between each polymorphism and adenoma. The high TGFB1 producer genotypes, -509TT and 10Pro/Pro, were associated with an increased risk of colorectal adenoma compared with other genotypes (OR = 1.51, 95% CI: 1.04-2.20 and OR = 1.37, 95% CI: 1.02-1.86, respectively). These increased risks, particularly for -509TT, were greater for persons with multiple adenomas (OR = 1.89, 95% CI: 1.16-3.09, P = 0.01) and individuals with rectal adenoma (OR = 2.95, 95% CI: 1.66-5.26, P = 0.0002). Haplotype analysis revealed similar findings under a recessive model. No associations were observed for polymorphisms at codons 25 and 263. In conclusion, variants that enhance TGFB1 production may be associated with an increased risk of advanced colorectal adenoma

IGF-1 and IGFBP-3 may influence risk of prostate cancer through their roles in cellular growth, metabolism and apoptosis, however, epidemiologic results have been inconsistent. The role of obesity in prostate cancer risk is not clearly understood, but hyperinsulinemia-related increases in bioactive IGF-1 levels, associated with obesity, could be a component of the relationship between the IGF-axis and prostate cancer. We conducted a nested case-control study in the prospective Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial to examine associations between IGF-1 and IGFBP-3 and risk of prostate cancer. A total of 727 incident prostate cancer cases and 887 matched controls were selected for this analysis. There was no clear overall association between IGF-1, IGFBP-3 and IGF-1:IGFBP-3 molar ratio (IGFmr) and prostate cancer risk, however, IGFmr was associated with risk in obese men (BMI > 30, p-trend = 0.04), with a greater than 2-fold increased risk in the highest IGFmr quartile (OR 2.34, 95% CI 1.10-5.01). Risk was specifically increased for aggressive disease in obese men (OR 2.80, 95% CI 1.11-7.08). In summary, our large prospective study showed no overall association between the insulin-like growth factor axis and prostate cancer risk, however, IGFmr was related to risk for aggressive prostate cancer in obese men