Faculty Bibliography

Background:Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.Methods:We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55-74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.Results:After adjusting for potential confounders, the hazard ratios (HRs) of prostate cancer associated with <1 and >/=1 pill of aspirin daily were 0.98 (95% confidence interval (CI), 0.90-1.07) and 0.92 (95% CI: 0.85-0.99), respectively, compared with never use (P for trend 0.04). The effect of taking at least one aspirin daily was more pronounced when restricting the analyses to men older than age 65 or men who had a history of cardiovascular-related diseases or arthritis (HR (95% CI); 0.87 (0.78-0.97), 0.89 (0.80-0.99), and 0.88 (0.78-1.00), respectively). The data did not support an association between ibuprofen use and prostate cancer risk.Conclusion:Daily aspirin use, but not ibuprofen use, was associated with lower risk of prostate cancer risk.

Genome-wide association studies (GWAS) have identified many single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. There is limited information on the mechanistic basis of these associations, particularly about whether they interact with circulating concentrations of growth factors and sex hormones, which may be important in prostate cancer etiology. Using conditional logistic regression, the authors compared per-allele odds ratios for prostate cancer for 39 GWAS-identified SNPs across thirds (tertile groups) of circulating concentrations of insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), testosterone, androstenedione, androstanediol glucuronide, estradiol, and sex hormone-binding globulin (SHBG) for 3,043 cases and 3,478 controls in the Breast and Prostate Cancer Cohort Consortium. After allowing for multiple testing, none of the SNPs examined were significantly associated with growth factor or hormone concentrations, and the SNP-prostate cancer associations did not differ by these concentrations, although 4 interactions were marginally significant (MSMB-rs10993994 with androstenedione (uncorrected P = 0.008); CTBP2-rs4962416 with IGFBP-3 (uncorrected P = 0.003); 11q13.2-rs12418451 with IGF-1 (uncorrected P = 0.006); and 11q13.2-rs10896449 with SHBG (uncorrected P = 0.005)). The authors found no strong evidence that associations between GWAS-identified SNPs and prostate cancer are modified by circulating concentrations of IGF-1, sex hormones, or their major binding proteins.

Periodontitis, the progressive loss of the alveolar bone around the teeth and the major cause of tooth loss in adults, is due to oral microorganisms, including Porphyromonas gingivalis. Periodontitis is associated with a local overly aggressive immune response and a spectrum of systemic effects, but the role of this condition in orodigestive cancers is unclear. We prospectively examined clinically ascertained periodontitis (N = 12 605) and serum IgG immune response to P.gingivalis (N = 7852) in relation to orodigestive cancer mortality among men and women in the National Health and Nutrition Examination Survey III. A detailed oral health exam was conducted from 1988 to 1994 in survey Phases I and II, whereas serum IgG for P.gingivalis was measured from 1991 to 1994 in Phase II only. One hundred and five orodigestive cancer deaths were ascertained through 31 December 2006. Periodontitis (moderate or severe) was associated with increased orodigestive cancer mortality [relative risks (RR) = 2.28, 95% confidence interval (CI) = 1.17-4.45]; mortality risks also increased with increasing severity of periodontal disease (P trend = 0.01). Periodontitis-associated mortality was in excess for colorectal (RR = 3.58; 95% CI = 1.15-11.16) and possibly for pancreatic cancer (RR = 4.56; 95% CI = 0.93-22.29). Greater serum P.gingivalis IgG tended to be associated overall with increased orodigestive cancer mortality (P trend = 0.06); P.gingivalis-associated excess orodigestive mortality was also found for healthy subjects not exhibiting overt periodontal disease (RR = 2.25; 95% CI = 1.23-4.14). Orodigestive cancer mortality is related to periodontitis and to the periodontal pathogen, P.gingivalis, independent of periodontal disease. Porphyromonas gingivalis is a biomarker for microbe-associated risk of death due to orodigestive cancer.

Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 x 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption. Cancer Res; 72(8); 2036-44. (c)2012 AACR.

A growing body of evidence implicates human oral bacteria in the etiology of oral and gastrointestinal cancers. Epidemiological studies consistently report increased risks of these cancers in men and women with periodontal disease or tooth loss, conditions caused by oral bacteria. More than 700 bacterial species inhabit the oral cavity, including at least 11 bacterial phyla and 70 genera. Oral bacteria may activate alcohol and smoking-related carcinogens locally or act systemically, through chronic inflammation. High-throughput genetic-based assays now make it possible to comprehensively survey the human oral microbiome, the totality of bacteria in the oral cavity. Establishing the association of the oral microbiome with cancer risk may lead to significant advances in understanding of cancer etiology, potentially opening a new research paradigm for cancer prevention.

Although recent studies have suggested that tooth loss is positively related to the risk of gastric non-cardia cancer, the underlying oral health conditions potentially responsible for the association remain unknown. We investigated whether clinical and behavioral measures of oral health are associated with the risk of gastric precancerous lesions. We conducted a cross-sectional study of 131 patients undergoing upper gastrointestinal endoscopy. Cases were defined as those with gastric precancerous lesions including intestinal metaplasia or chronic atrophic gastritis on the basis of standard biopsy review. A validated structured questionnaire was administered to obtain information on oral health behaviors. A comprehensive clinical oral health examination was performed on a subset of 91 patients to evaluate for periodontal disease and dental caries experience. A total of 41 (31%) cases of gastric precancerous lesions were identified. Compared with non-cases, cases were significantly more likely to not floss their teeth [odds ratio (OR) = 2.89, 95% confidence interval (CI): 1.09-7.64], adjusting for age, sex, race, body mass index, smoking status, educational attainment and Helicobacter pylori status in serum. Among participants who completed the oral examination, cases (n = 28) were more likely to have a higher percentage of sites with gingival bleeding than non-cases [OR = 2.63, 95% CI: 1.37-5.05 for a standard deviation increase in bleeding sites (equivalent to 19.7%)], independent of potential confounders. Our findings demonstrate that specific oral health conditions and behaviors such as gingival bleeding and tooth flossing are associated with gastric precancerous lesions.

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 x 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 x 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 x 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer

Background: Occupational exposure to nickel is associated with an increased risk for lung and nasal cancers. Nickel compounds exhibit weak mutagenic activity, cause gene amplification, and disrupt cellular epigenetic homeostasis. However, the nickel-induced changes in global histone modification levels have only been tested in vitro. Objective: This study was conducted in a Chinese population to determine whether occupational exposure to nickel is associated with alterations of global histone modification levels and to evaluate the inter-and intra-individual variance of global histone modification levels. Method: 45 subjects with occupational exposure to nickel and 75 referents were recruited. Urinary nickel and global H3K4 trimethylation (H3K4me3), H3K9 acetylation (H3K9ac), and H3K9 dimethylation (H3K9me2) levels were measured in peripheral blood mononuclear cells (PBMCs) of subjects. Results: H3K4me3 was elevated (0.25%+/-0.11%, 0.15%+/-0.04%, p=0.0004) and H3K9me2 was decreased (0.11%+/-0.05%, 0.15%+/-0.04%, p=0.003) in Ni-exposed subjects. H3K4me3 was positively (r=0.4, p=0.0008) and H3K9ac was negatively (r=0.1, p=0.01) associated with urinary nickel. Inter-individual variances of H3K4me3, H3K9ac, and H3K9me2 were larger relative to intra-individual variance in both groups, resulting in reliability coefficients, estimate of consistency of a set of measurements, of 0.75, 0.74, and 0.97 for H3K4me3, H3K9ac, and H3K9me2, respectively, for referent subjects. Reliability coefficients of 0.60, 0.67, and 0.79 were found for H3K4me3, H3K9ac, and H3K9me2, respectively, for Ni-exposed subjects. Conclusion: The results of this study indicate that occupational exposure to nickel is associated with alterations of global histone modification levels and that measurements of global levels of histone modifications are relatively stable over time in human PBMCs

BACKGROUND: Most studies of meat and colorectal adenoma have investigated prevalent events from a single screening, thus limiting our understanding of the role of meat and meat-related exposures in early colorectal carcinogenesis. METHODS: Among participants in the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who underwent baseline and follow-up sigmoidoscopy (n=17,072), we identified 1008 individuals with incident distal colorectal adenoma. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between meat and meat-related components and incident distal colorectal adenoma using multivariate logistic regression. RESULTS: We observed suggestive positive associations for red meat, processed meat, haeme iron, and nitrate/nitrite with distal colorectal adenoma. Grilled meat (OR=1.56, 95% CI=1.04-2.36), well or very well-done meat (OR=1.59, 95% CI=1.05-2.43), 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP) (OR=1.75, 95% CI=1.17-2.64), benzo[a]pyrene (OR=1.53, 95% CI=1.06-2.20), and total mutagenic activity (OR=1.57, 95% CI=1.03-2.40) were positively associated with rectal adenoma. Total iron (diet and supplements) (OR=0.69, 95% CI=0.56-0.86) and iron from supplements (OR=0.65, 95% CI=0.44-0.97) were inversely associated with any distal colorectal adenoma. CONCLUSION: Our findings indicate that several meat-related components may be most relevant to early neoplasia in the rectum. In contrast, total iron and iron from supplements were inversely associated with any distal colorectal adenoma.

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97)