Faculty Bibliography

OBJECTIVES: To determine the association between prostatic enlargement and a cytosine for thymine genetic polymorphism at nucleotide 154 (C154T) of the NKX3.1 prostate homeobox gene. The polymorphism, found in 10% of the population, affects the NKX3.l protein by replacing a cysteine for arginine at amino acid 52 and alters protein phosphorylation and DNA binding. METHODS: A study group of men without prostate cancer from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial was identified who had had at least three annual serial digital rectal examinations by a single examiner. The cohort of 772 men consisted of the lowest and highest tertiles of the entire study group as defined by two-dimensional measurements at digital rectal examination. The TaqMan allelic discrimination assay was used to genotype NKX3.1 for the nucleotide 154 polymorphism. RESULTS: The men in the lower tertile (n = 413) had a mean age of 60.8 years, mean prostate-specific antigen level of 1.2 ng/mL, and mean prostate volume of 37.9 +/- 4.5 cm3. The men in the upper tertile (n = 359) had a mean age of 61.6 years, mean prostate-specific antigen level of 2.1 ng/mL, and mean prostate volume of 61 +/- 6.3 cm3. The men in the upper tertile had a greater likelihood of having a clinical history of benign prostatic hyperplasia and more frequent nocturia. The presence of one or two polymorphic NKX3.1 alleles conferred a risk of 1.6 (95% confidence interval 1.0 to 2.6) for an enlarged prostate (highest tertile). CONCLUSIONS: The NKX3.1 nucleotide 154 C/T or T/T genotype increases the relative odds for prostatic enlargement. The group with prostatic enlargement also had increased clinical benign prostatic hyperplasia and nocturia

This study expands a previous study of NAT2 polymorphisms and bladder cancer in male subjects occupationally exposed only to benzidine. The combined analysis of 68 cases and 107 controls from a cohort of production workers in China exposed to benzidine included 30 new cases and 67 controls not previously studied. NAT2 enzymatic activity phenotype was characterized by measuring urinary caffeine metabolite ratios. PCR-based methods identified genotypes for NAT2, NAT1 and GSTM1. NAT2 phenotype and genotype data were consistent. A protective association was observed for the slow NAT2 genotype (bladder cancer OR = 0.3; 95% CI = 0.1 = 1.0) after adjustment for cumulative benzidine exposure and lifetime smoking. Individuals carrying NAT1wt/*10 and NAT1*10/*10 showed higher relative risks of bladder cancer (OR = 2.8, 95% CI = 0.8-10.1 and OR = 2.2, 95% CI = 0.6-8.3, respectively). No association was found between GSTM1 null and bladder cancer. A metaanalysis risk estimate of case-control studies of NAT2 acetylation and bladder cancer in Asian populations without occupational arylamine exposures showed an increased risk for slow acetylators. The lower limit of the confidence interval (OR = 1.4; 95% CI = 1.0-2.0) approximated the upper confidence interval for the estimate obtained in our analysis. These results support the earlier finding of a protective association between slow acetylation and bladder cancer in benzidine-exposed workers, in contrast to its established link as a risk factor for bladder cancer in people exposed to 2-naphthylamine and 4-aminobiphenyl. Study findings suggest the existence of key differences in the metabolism of mono- and diarylamines

BACKGROUND: Dietary lycopene and tomato products may reduce risk of prostate cancer; however, uncertainty remains about this possible association.METHODS: We evaluated the association between intake of lycopene and specific tomato products and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to investigate cancer early detection methods and etiologic determinants. Participants completed both a general risk factor and a 137-item food frequency questionnaire at baseline. A total of 1,338 cases of prostate cancer were identified among 29,361 men during an average of 4.2 years of follow-up.RESULTS: Lycopene intake was not associated with prostate cancer risk. Reduced risks were also not found for total tomato servings or for most tomato-based foods. Statistically nonsignificant inverse associations were noted for pizza [all prostate cancer: relative risk (RR), 0.83; 95% confidence interval (95% CI), 0.67-1.03 for >or=1 serving/wk versus < 0.5 serving/mo; P(trend)=0.06 and advanced prostate cancer: RR, 0.79; 95% CI, 0.56-1.10; P(trend)=0.12] and spaghetti/tomato sauce consumption (advanced prostate cancer: RR=0.81, 95% CI, 0.57-1.16 for >or=2 servings/wk versus<1 serving/mo; P(trend)=0.31). Among men with a family history of prostate cancer, risks were decreased in relation to increased consumption of lycopene (P(trend)=0.04) and specific tomato-based foods commonly eaten with fat (spaghetti, P(trend)=0.12; pizza, P(trend)=0.15; lasagna, P(trend)=0.02).CONCLUSIONS: This large study does not support the hypothesis that greater lycopene/tomato product consumption protects from prostate cancer. Evidence for protective associations in subjects with a family history of prostate cancer requires further corroboration

With the rapid development of biomarkers and new technologies, large-scale biologically-based cohort studies present expanding opportunities for population-based research on disease etiology and early detection markers. The prostate, lung, colorectal and ovarian cancer (PLCO) screening trial is a large randomized trial designed to determine if screening for these cancers leads to mortality reduction for these diseases. Within the Trial, the PLCO etiology and early marker study (EEMS) identifies risk factors for cancer and other diseases and evaluates biologic markers for the early detection of disease. EEMS includes 155,000 volunteers who provide basic risk factor information. Serial blood samples are collected at each of six screening rounds (including one collection for cryopreserved whole blood) from screening arm participants (77,000 subjects) and buccal cells are collected from those in the control arm of the trial. Etiologic studies consider environmental (e.g., diet), biochemical, and genetic factors. Early detection studies focus on blood-based biologic markers of early disease. Clinical epidemiology is also an important component of the PLCO trial

High-temperature cooked meat contains heterocyclic amines, including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and polycyclic aromatic hydrocarbons, such as benzo(a)pyrene (BaP). In rodents, a high intake of PhIP induces prostate tumors. We prospectively investigated the association between meat and meat mutagens, specifically PhIP, and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Diet was assessed using a 137-item food frequency questionnaire and a detailed meat-cooking questionnaire linked to a database for BaP and the heterocyclic amines 2-amino-3,8-dimethylimidazo[4,5-b]quinoxaline (MeIQx), 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and PhIP. During follow-up, we ascertained a total of 1,338 prostate cancer cases among 29,361 men; of these, 868 were incident cases (diagnosed after the first year of follow-up) and 520 were advanced cases (stage III or IV or a Gleason score of > or =7). Total, red, or white meat intake was not associated with prostate cancer risk. More than 10 g/d of very well done meat, compared with no consumption, was associated with a 1.4-fold increased risk of prostate cancer [95% confidence interval (95% CI), 1.05-1.92] and a 1.7-fold increased risk (95% CI, 1.19-2.40) of incident disease. Although there was no association with MeIQx and DiMeIQx, the highest quintile of PhIP was associated with a 1.2-fold increased risk of prostate cancer (95% CI, 1.01-1.48) and a 1.3-fold increased risk of incident disease (95% CI, 1.01-1.61). In conclusion, very well done meat was positively associated with prostate cancer risk. In addition, this study lends epidemiologic support to the animal studies, which have implicated PhIP as a prostate carcinogen

OBJECTIVES/HYPOTHESIS: We tested the hypothesis that polymorphisms in genes involved in DNA repair pathways are associated with the development of second primary neoplasms of the upper aerodigestive tract (UADT), as well as mortality, in patients previously diagnosed with oral squamous cell cancer (OSCC). METHODS: DNA specimens from 279 OSCC patients who had participated in two previous population-based case-control studies were assayed for the following polymorphisms: X-ray repair cross-complementing (XRCC) 1 Arg399Gln, XRCC3 Thr241Met, xeroderma pigmentosum complementing group D (XPD) Lys751Gln, and O-methylguanine- DNA methyltransferase (MGMT) Leu84Phe and Val143Ile. Baseline demographic information was obtained from personal interviews and tumor characteristics and treatment were obtained from cancer registry files. Cox proportional hazards models were used to calculate hazards ratio (HR) estimates for each polymorphism in relation to the risk of developing second primary neoplasms at any site, UADT, and head and neck. HRs were also determined for associations with all-cause mortality and oral cancer specific mortality. RESULTS: A significant increased risk of second neoplasms (all sites combined, as well as for UADT sites and for head and neck squamous cell cancers) was observed among XRCC3 241Met allele homozygotes (HR 2.65-3.44, P < .02). No significant association with the development of second neoplasms was observed for the XRCC1 399Gln, XPD 751Gln, or MGMT 84Phe or 143Ile alleles. Although no associations with oral cancer-specific mortality were observed, we found a significant inverse association between all-cause mortality and possessing at least one copy of the XRCC1 399Gln allele (HR 0.68, 95% confidence interval [CI] 0.47-0.97, P = .03), as well as a suggestion of a direct association between all-cause mortality and having one copy of the XRCC3 241Met allele (HR 1.39, 95% CI 0.95-2.03, P = .09). CONCLUSIONS: Polymorphisms in the DNA repair enzyme gene XRCC3 241Met was associated with an increased risk of second neoplasms, and polymorphisms of the XRCC1 399Gln gene were associated with a decreased risk of all-cause mortality in patients with primary OSCC. These findings require confirmation in other populations before the clinical implications can be considered

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17beta-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Delta5-androsterone-3beta,17beta-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites

Benzene is a recognized hematotoxin and leukemogen but its mechanism of action and the role of genetic susceptibility are still unclear. Cytokines, chemokines, and cellular adhesion molecules are soluble proteins that play an important regulatory role in hematopoiesis. We therefore hypothesized that variation in these genes could influence benzene-induced hematotoxicity. We analyzed common, well-studied single-nucleotide polymorphisms (SNPs) in 20 candidate genes drawn from these pathways in a study of 250 workers exposed to benzene and 140 unexposed controls in China. After accounting for multiple comparisons, SNPs in five genes were associated with a statistically significant decrease in total WBC counts among exposed workers [IL-1A (-889C>T), IL-4 (-1098T>G), IL-10 (-819T>C), IL-12A (8685G>A), and VCAM1 (-1591T>C)], and one SNP [CSF3 (Ex4-165C>T)] was associated with an increase in WBC counts. The adhesion molecule VCAM1 variant was particularly noteworthy as it was associated with a decrease in B cells, natural killer cells, CD4+ T cells, and monocytes. Further, VCAM1 (-1591T>C) and CSF3 (Ex4-165C>T) were associated, respectively, with decreased (P = 0.041) and increased (P = 0.076) CFU-GEMM progenitor cell colony formation in 29 benzene-exposed workers. This is the first report to provide evidence that SNPs in genes that regulate hematopoiesis influence benzene-induced hematotoxicity

OBJECTIVE: Findings from some epidemiologic studies of colorectal cancer and adenoma suggest that the protective effect of post-menopausal hormone replacement therapy (HRT) may differ across categories of age and body mass index (BMI). We conducted an analysis of women participating in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to investigate the relationship between HRT use and prevalent adenoma, both overall and across different population subgroups. METHODS: Women aged 55-74 were randomized to screening by flexible sigmoidoscopy at ten PLCO screening centers between September 1993 and September 2001. We identified 1468 women with at least one left-sided adenoma and 19,203 without adenoma or colorectal cancer. Information about HRT and reproductive factors was obtained from a self-administered questionnaire. RESULTS: Compared to never use of HRT, current use was associated with a decreased prevalence of left-sided adenoma (odds ratio (OR) 0.85; 95% confidence interval (CI) 0.75-0.97). We found no evidence of dose-response with increasing duration of use for current or former users. The association with current HRT use was stronger among women aged 65+ (OR 0.69; 95% CI 0.56-0.84), with a BMI<30 (OR 0.82; 95% CI 0.71-0.95) and who regularly use aspirin or ibuprofen (OR 0.77; 95% CI 0.65-0.91). Other reproductive factors were not significantly associated with adenoma prevalence. CONCLUSIONS: Our findings suggest that current HRT use may protect against colorectal adenoma, and that this protective effect is short-lived following cessation of use