Faculty Bibliography

PURPOSE: We previously reported an inverse association between flavonoid intake and breast cancer incidence, which has been confirmed by others, but no studies have considered simultaneously potential interactions of flavonoids with multiple genetic polymorphisms involved in biologically relevant pathways (oxidative stress, carcinogen metabolism, DNA repair, and one-carbon metabolism). METHODS: To estimate interaction effects between flavonoids and 13 polymorphisms in these four pathways on breast cancer risk, we used population-based data (n = 875 cases and 903 controls) and several statistical approaches, including conventional logistic regression and semi-Bayesian hierarchical modeling (incorporating prior information on the possible biologic functions of genes), which also provides biologic pathway-specific effect estimates. RESULTS: Compared to the standard multivariate model, the results from the hierarchical model indicate that gene-by-flavonoid interaction estimates are attenuated, but more precise. In the hierarchical model, the average effect of the deleterious versus beneficial gene, controlling for average flavonoid intake in the DNA repair pathway, and adjusted for the three other biologically relevant pathways (oxidative stress, carcinogen metabolism, and one-carbon metabolism), resulted in a 27 % increase risk for breast cancer [odds ratio = 1.27; 95 % confidence interval (CI) = 0.70, 2.29]. However, the CI was wide. CONCLUSIONS: Based on results from the semi-Bayesian model, breast cancer risk may be influenced jointly by flavonoid intake and genes involved in DNA repair, but our findings require confirmation.

The oral micro biome is highly diverse and its composition is associated with oral disease and potentially diseases at other sites. Our objective is to evaluate DNA extraction methods potentially suitable for population-based investigations on the oral human microbiome and disease risk. Six commonly used microbial DNA extraction kits, employing either enzymatic methods or mechanical bead beating for cell lysis, were evaluated for the following aspects total DNA yield and quality and 16s rRNA DNA product and representation of microbial diversity. All analyses were carried out using a pooled and homogenized sample from one study subject. 16s rRNA gene sequence data were processed using the QIIME pipeline. One way ANOVA and Kruskal-Wallis tests were used to compare the different DNA extraction methods. We found that enzymatic extraction kits produced higher human genomic DNA, compared with mechanical extraction kits, however, phylogenic diversity in oral microbiome community structure from 16s rRNA gene sequence reads revealed no important differences between kit types. Enzymatic and mechanical bead beating kits provide alternative approaches for DNA extraction of oral microbiome DNA from oral wash samples. Greater total DNA yields are found in enzymatic approaches but microbial diversity can be similarly well characterized by either enzymatic or mechanical bead beating approaches

We tested the hypothesis that an altered community of gut microbes is associated with risk of colorectal cancer (CRC) in a study of 47 CRC case subjects and 94 control subjects. 16S rRNA genes in fecal bacterial DNA were amplified by universal primers, sequenced by 454 FLX technology, and aligned for taxonomic classification to microbial genomes using the QIIME pipeline. Taxonomic differences were confirmed with quantitative polymerase chain reaction and adjusted for false discovery rate. All statistical tests were two-sided. From 794217 16S rRNA gene sequences, we found that CRC case subjects had decreased overall microbial community diversity (P = .02). In taxonomy-based analyses, lower relative abundance of Clostridia (68.6% vs 77.8%) and increased carriage of Fusobacterium (multivariable odds ratio [OR] = 4.11; 95% confidence interval [CI] = 1.62 to 10.47) and Porphyromonas (OR = 5.17; 95% CI = 1.75 to 15.25) were found in case subjects compared with control subjects. Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for CRC prevention.

Background:Coffee and tea are commonly consumed and carry potential anticancer components that could reduce the risk of colorectal cancer; however, their relationships with colorectal cancer risk remain inconsistent.Methods:A prospective analysis was carried out to examine the relationships of coffee and tea intake with colorectal cancer risk in 57 398 men and women in the intervention arm of the National Cancer Institute-Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, a national screening study that limits differential detection biases. Coffee and tea intakes were assessed by food frequency questionnaire.Results:Six hundred and eighty-one incident colorectal cancer cases were ascertained during a median follow-up of 11.4 years. Greater coffee intake was not associated with risk of colorectal cancer (relative risk (RR)=1.08, 95% confidence interval (CI)=0.79-1.48, Ptrend=0.23). Stratifying by cancer site (Pheterogeneity=0.48) or stage (Pheterogeneity=0.83) did not alter the relationship. Associations remained unchanged in subsets of participants for either caffeinated or decaffeinated coffee or when stratifying by several colorectal cancer risk factors. Similarly, greater tea intake was not associated with colorectal cancer risk overall (RR=0.77, 95% CI=0.55-1.09, Ptrend=0.17) or by cancer site (Pheterogeneity=0.14) or stage (Pheterogeneity=0.60). These associations were not modified by several colorectal cancer risk factors.Conclusion:The findings of this study do not provide evidence to suggest that drinking coffee or tea is beneficial in protecting against colorectal cancer.

OBJECTIVE: Obesity is a risk factor for cardiovascular disease (CVD) mortality, but the association between obesity and specific causes of CVD mortality is still under investigation. METHOD: We prospectively examined body-mass index (BMI) in relation to CVD-specific causes of death in approximately 86,000 US men and women in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, followed for up to 13years. BMI was calculated from self-reported weight and height at baseline. Hazard ratios (HRs) were calculated overall and stratified by sex, smoking status, and educational level. RESULT: Overweight non-obese participants (BMI: 25.0-29.9) were not at excess risk for CVD mortality (HR and CIs are 1.02 [0.92-1.13]), compared to participants of normal BMI (18.5-24.9). Excess CVD mortality was observed for participants of BMI 30.0-34.9 (HR and CIs: 1.29 [1.13-1.48]), BMI 35.0-39.9 (HR and CIs: 1.87 [1.51-2.32]) and BMI 40.0+ (HR and CIs: 2.21 [1.57-3.21]) (p<0.001 for trend). BMI was unrelated to mortality due to stroke. The observed association of BMI with CVD was independent of gender, smoking status and educational level. CONCLUSION: Obesity is associated with increased mortality due to CVD.

PURPOSE: The mechanisms driving the physical activity-breast cancer association are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Given the paradoxical effects of physical activity, the oxidative stress pathway is of interest. Genetic variation in CAT or antioxidant-related polymorphisms may mediate the physical activity-breast cancer association. METHODS: We investigated the main and joint effects of three previously unreported polymorphisms in CAT on breast cancer risk. We also estimated interactions between recreational physical activity (RPA) and 13 polymorphisms in oxidative stress-related genes. Data were from the Long Island Breast Cancer Study Project, with interview and biomarker data available on 1,053 cases and 1,102 controls. RESULTS: Women with >/=1 variant allele in CAT rs4756146 had a 23 % reduced risk of postmenopausal breast cancer compared with women with the common TT genotype (OR = 0.77; 95 % CI = 0.59-0.99). We observed two statistical interactions between RPA and genes in the antioxidant pathway (p = 0.043 and 0.006 for CAT and GSTP1, respectively). Highly active women harboring variant alleles in CAT rs1001179 were at increased risk of breast cancer compared with women with the common CC genotype (OR = 1.61; 95 % CI, 1.06-2.45). Risk reductions were observed among moderately active women carrying variant alleles in GSTP1 compared with women homozygous for the major allele (OR = 0.56; 95 % CI, 0.38-0.84). CONCLUSIONS: Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation.

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.

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.