Faculty Bibliography

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.

BACKGROUND: Vitamin E compounds exhibit prostate cancer preventive properties experimentally, but serologic investigations of tocopherols, and randomized controlled trials of supplementation in particular, have been inconsistent. Many studies suggest protective effects among smokers and for aggressive prostate cancer, however. METHODS: We conducted a nested case-control study of serum alpha-tocopherol and gamma-tocopherol and prostate cancer risk in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, with 680 prostate cancer cases and 824 frequency-matched controls. Multivariate-adjusted, conditional logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CIs) for tocopherol quintiles. RESULTS: Serum alpha-tocopherol and gamma-tocopherol were inversely correlated (r = -0.24, p<0.0001). Higher serum alpha-tocopherol was associated with significantly lower prostate cancer risk (OR for the highest vs. lowest quintile = 0.63, 95% CI 0.44-0.92, p-trend 0.05). By contrast, risk was non-significantly elevated among men with higher gamma-tocopherol concentrations (OR for the highest vs. lowest quintile = 1.35, 95% CI 0.92-1.97, p-trend 0.41). The inverse association between prostate cancer and alpha-tocopherol was restricted to current and recently former smokers, but was only slightly stronger for aggressive disease. By contrast, the increased risk for higher gamma-tocopherol was more pronounced for less aggressive cancers. CONCLUSIONS: Our findings indicate higher alpha-tocopherol status is associated with decreased risk of developing prostate cancer, particularly among smokers. Although two recent controlled trials did not substantiate an earlier finding of lower prostate cancer incidence and mortality in response to supplementation with a relatively low dose of alpha-tocopherol, higher alpha-tocopherol status may be beneficial with respect to prostate cancer risk among smokers. Determining what stage of prostate cancer development is impacted by vitamin E, the underlying mechanisms, and how smoking modifies the association, is needed for a more complete understanding of the vitamin E-prostate cancer relation.

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.

Vitamin D deficiency has been shown to be associated with multiple clinical outcomes, including osteoporosis, multiple sclerosis and colorectal cancer. In studies of vitamin D effect on disease outcome, vitamin D status is usually measured by a serum biomarker, namely 25-hydroxy vitamin D [25(OH)D]. Since the circulating 25(OH)D concentration varies from season to season and not all blood samples are collected at the same time, the disease-vitamin D relationship can be obscured if the seasonal variation is not adjusted properly. In the literature, a two-step procedure is usually adopted, with the vitamin D level adjusted for the seasonal variation being obtained in the first step, and the effect of vitamin D being assessed based on the adjusted vitamin D level at the second step. This two-step method can generate misleading results as the estimation variance arising from the first step is not taken into account in the second step analysis. We consider three alternative procedures that unify the two steps into a single model. We conduct an extensive simulation study to evaluate the performance of these methods and demonstrate their applications in a study of 25(OH)D effect on prostate cancer risk.

Though dietary factors are implicated in chronic disease risk, assessment of dietary intake has limitations, including problems with recall of complex food intake patterns over a long period of time. Diet and nutrient biomarkers may provide objective measures of dietary intake and nutritional status, as well as an integrated measure of intake, absorption and metabolism. Thus, the search for an unbiased biomarker of dietary intake and nutritional status is an important aspect of nutritional epidemiology. This chapter reviews types of biomarkers related to dietary intake and nutritional status, such as exposure biomarkers of diet and nutritional status, intermediate endpoints, and susceptibility. Novel biomarkers, such as biomarkers of physical fitness, oxidative DNA damage and tissue concentrations are also discussed.

OBJECTIVES: The human oral microbiome is potentially related to diverse health conditions and high-throughput technology provides the possibility of surveying microbial community structure at high resolution. We compared two oral microbiome survey methods: broad-based microbiome identification by 16S rRNA gene sequencing and targeted characterization of microbes by custom DNA microarray. METHODS: Oral wash samples were collected from 20 individuals at Memorial Sloan-Kettering Cancer Center. 16S rRNA gene survey was performed by 454 pyrosequencing of the V3-V5 region (450 bp). Targeted identification by DNA microarray was carried out with the Human Oral Microbe Identification Microarray (HOMIM). Correlations and relative abundance were compared at phylum and genus level, between 16S rRNA sequence read ratio and HOMIM hybridization intensity. RESULTS: The major phyla, Firmicutes, Proteobacteria, Bacteroidetes, Actinobacteria, and Fusobacteria were identified with high correlation by the two methods (r = 0.70 approximately 0.86). 16S rRNA gene pyrosequencing identified 77 genera and HOMIM identified 49, with 37 genera detected by both methods; more than 98% of classified bacteria were assigned in these 37 genera. Concordance by the two assays (presence/absence) and correlations were high for common genera (Streptococcus, Veillonella, Leptotrichia, Prevotella, and Haemophilus; Correlation = 0.70-0.84). CONCLUSION: Microbiome community profiles assessed by 16S rRNA pyrosequencing and HOMIM were highly correlated at the phylum level and, when comparing the more commonly detected taxa, also at the genus level. Both methods are currently suitable for high-throughput epidemiologic investigations relating identified and more common oral microbial taxa to disease risk; yet, pyrosequencing may provide a broader spectrum of taxa identification, a distinct sequence-read record, and greater detection sensitivity.

Objectives: To determine if cigarette smoking and oral squamous cell carcinoma (OSCC) are associated with an alteration of the oral microbiome, and to determine if the oral microbiome is capable of activating cigarette carcinogens. Methods: Oral wash samples were collected from 9 patients with OSCC and 10 non-cancer controls (including 5 smokers and 5 non-smokers). Bacterial DNA was isolated from each oral wash and then 16S rRNA gene survey performed by 454 pyrosequencing of the V3-5 region to identify bacterial sequences present in oral wash samples. Bacterial sequences present in OSCC patient samples and in control patient samples were then categorized. Also, a mock community, composed of 5 bacterial species found in the oral microbiome, was tested for its ability to metabolize cigarette carcinogens. Results: Samples of the oral microbiome were classified into type I and type II microbiomes, based on taxonomic similarity between samples. The type I microbiome was dominated by Grampositive bacteria whereas the type II microbiome was dominated by Gram-negative bacteria. Non-cancer control patients had the type I microbiome (9/10). In contrast, OSCC patients had the type II microbiome (6/9). Furthermore, OSCC was associated with an apparent decrease in the relative abundance of Streptococcus (22.3%) compared with non-smoking (39.4%) and smoking controls (40.1%). There was a step-wise increase in the relative abundance of Veilonella along the non-smoking controls (2.3%) -> smoking controls (6.8%) -> OSCC (9.9%) sequence. Metabolomic analysis demonstrated that a mock bacterial community composed of Streptococcus mitis and Veilonella dispar was able to hydroxylate N-nitrosodieth-ylamine and degrade p-chloroaniline, both being carcinogens found in cigarette smoke. Conclusions: Cigarette smoking and oral squamous cell carcinoma are associated with an alteration of the oral microbiome. The oral microbiome has the potential to modulate oral cancer risk by activating cigarette carcinogens

PURPOSE: Genome-wide association studies (GWAS) have identified multiple novel prostate cancer predisposition loci. Whether these common genetic variants are associated with incident metastatic prostate cancer or with recurrence after surgical treatment for clinically localized prostate cancer is uncertain. EXPERIMENTAL DESIGN: Twelve single nucleotide polymorphisms (SNPs) were selected for study in relation to prostate metastatic cancer and recurrence, based on their genome-wide association with prostate cancer in the Cancer Genetic Markers of Susceptibility (CGEMS). To assess risk for metastatic disease, we compared genotypes for the 12 SNPs by logistic regression of 470 incident metastatic prostate cancer cases and 1,945 controls in 3 case-control studies. To assess the relationship of these SNPs to risk for prostate cancer recurrence, we used Cox regression in a cohort of 1,412 men treated for localized prostate cancer, including 328 recurrences, and used logistic regression in a case-case study, comparing 450 recurrent versus 450 nonrecurrent prostate cancer cases. Study-specific relative risks (RRs) for risk of metastatic disease and recurrence were summarized using meta-analysis, with inverse variance weights. RESULTS: MSMB rs10993994 (per variant allele summary RR = 1.24, 95% CI = 1.05-1.48), 8q24 rs4242382 (RR = 1.40, 95% CI = 1.13-1.75), and 8q24 rs6983267 (RR = 0.67, 95% CI = 0.50-0.89) were associated with risk for metastatic prostate cancer. None of the 12 SNPs was associated with prostate cancer recurrence. CONCLUSIONS: SNPs in MSMB and 8q24 which predispose to prostate cancer overall are associated with risk for metastatic prostate cancer, the most lethal form of this disease. SNPs predictive of prostate cancer recurrence were not identified, among the predisposition SNPs. GWAS specific to these 2 phenotypes may identify additional phenotype-specific genetic determinants