Faculty Bibliography

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol-CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from five case-control and 11 nested case-control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study-specific results were pooled using fixed-effects meta-analysis. Compared to non-/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (OR: 0.92, 95% CI: 0.88-0.98, p = 0.005), heavy drinking (2-3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99-1.24, p = 0.08), and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11-1.40, p < 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J-shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

Inter-individual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value=3.5x10^-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value=5.7x10^-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8x10^-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g. rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis. This article is protected by copyright. All rights reserved.

Mounting evidence indicates that coffee, a commonly consumed beverage worldwide, is inversely associated with various chronic diseases and overall mortality. Few studies have evaluated the effect of coffee drinking on telomere length, a biomarker of chromosomal integrity, and results have been inconsistent. Understanding this association may provide mechanistic insight into associations of coffee with health. The aim of our study was to test the hypothesis that heavier coffee intake is associated with greater likelihood of having above-median telomere length. We evaluated the cross-sectional association between coffee intake and relative telomere length using data from 1,638 controls from four previously conducted case-control studies nested in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Coffee intake was assessed using a food frequency questionnaire, and relative telomere length was measured from buffy-coat, blood, or buccal cells. We used unconditional logistic regression models to generate multivariable-adjusted, study-specific odds ratios for the association between coffee intake and relative telomere length. We then conducted a random-effects meta-analysis to determine summary odds ratios. We found that neither summary continuous (OR = 1.01, 95% CI = 0.99-1.03) nor categorical (OR <3 cups/day vs. none = 1.37, 95% CI = 0.71-2.65; OR ≥3 cups/day vs. none = 1.47, 95% CI = 0.81-2.66) odds ratio estimates of coffee drinking and relative telomere length were statistically significant. However, in the largest of the four contributing studies, moderate (<3 cups/day) and heavy coffee drinkers (≥3 cups/day) were 2.10 times (95% CI = 1.25, 3.54) and 1.93 times as likely (95% CI = 1.17, 3.18) as nondrinkers to have above-median telomere length, respectively. In conclusion, we found no evidence that coffee drinking is associated with telomere length. Thus, it is unlikely that telomere length plays a role in potential coffee-disease associations.

OBJECTIVE:Early-onset colorectal cancer (CRC) is increasing in the USA despite rapid declines in older ages. Similar patterns are reported in Australia and Canada, but a comprehensive global analysis of contemporary data is lacking. DESIGN/METHODS:We extracted long-term data from Cancer Incidence in Five Continents and supplemental sources to report on worldwide CRC incidence rates and trends by age (20-49 years and ≥50 years) through diagnosis year 2012 or beyond (Australia, Finland, New Zealand, Norway, Sweden, USA). RESULTS:During 2008-2012, age-standardised CRC incidence rates in adults <50 ranged from 3.5 per 100 000 (95% CI 3.2 to 3.9) in India (Chennai) to 12.9 (95% CI 12.6 to 13.3) in Korea. During the most recent decade of available data, incidence in adults <50 was stable in 14 of 36 countries; declined in Austria, Italy and Lithuania; and increased in 19 countries, nine of which had stable or declining trends in older adults (Australia, Canada, Denmark, Germany, New Zealand, Slovenia, Sweden, UK and USA). In Cyprus, Netherlands and Norway, inclines in incidence in young adults were twice as rapid as those in older adults (eg, Norway average annual per cent change (AAPC), 1.9 (95% CI 1.4 to 2.5) vs 0.5 (95% CI 0.3 to 0.7)). Among most high-income countries with long-term data, the uptick in early-onset disease began in the mid-1990s. The steepest increases in young adults were in Korea (AAPC, 4.2 (95% CI 3.4 to 5.0)) and New Zealand (AAPC, 4.0 (95% CI 2.1 to 6.0)). CONCLUSION/CONCLUSIONS:CRC incidence increased exclusively in young adults in nine high-income countries spanning three continents, potentially signalling changes in early-life exposures that influence large bowel carcinogenesis.

RATIONALE/BACKGROUND:Many studies have linked short-term exposure to ozone (O3) with morbidity and mortality, but epidemiological evidence of associations between long-term ozone exposure and mortality is more limited. OBJECTIVES/OBJECTIVE:We investigated associations of long-term (annual or warm season average) O3 exposure with all-cause and cause-specific mortality in the NIH-AARP Diet and Health Study, a large prospective cohort of U.S. adults with 17 years of follow-up from 1995 to 2011. METHODS:The cohort (N=548,780) was linked to census tract-level estimates for O3. Associations between long-term O3 exposure (averaged values from 2002-2010) and multiple causes of death were evaluated using multivariate Cox proportional hazards models, adjusted for both individual- and census tract-level covariates, as well as potentially confounding co-pollutants and temperature. MEASUREMENTS AND MAIN RESULTS/RESULTS:Long-term annual average exposure to O3 was significantly associated with deaths due to cardiovascular disease (per 10 ppb, HR=1.03; 95% CI: 1.01-1.06), ischemic heart disease (HR=1.06; 95% CI: 1.02-1.09), respiratory disease (HR=1.04; 95% CI: 1.00-1.09), and chronic obstructive pulmonary disease (HR=1.09; 95% CI: 1.03-1.15) in single-pollutant models. The results were robust to alternative models and adjustment for co-pollutants (fine particulate matter and nitrogen dioxide), although some evidence of confounding by temperature was observed. Significantly elevated respiratory disease mortality risk associated with long-term O3 exposure was found among those living in locations with high temperature (p-interaction<0.05). CONCLUSIONS:This study found that long-term exposure to O3 is associated with increased risk for multiple causes of mortality, suggesting that establishment of annual and/or seasonal federal O3 standard(s) are needed to more adequately protect public health from ambient O3 exposures.

BACKGROUND:Tobacco use is a well-established risk factor for head and neck cancer (HNC). However, less is known about the potential impact of exposure to tobacco at an early age on HNC risk. METHODS:We analyzed individual-level data on ever tobacco smokers from 27 case-control studies (17,146 HNC cases and 17,449 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) consortium. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using random-effects logistic regression models. RESULTS:: 0.97, 95% CI: 0.80, 1.19). In the stratified analyses on HNC subsites by tobacco packyears or years since quitting, no difference in the association between age at start and HNC risk was observed. CONCLUSIONS:Results from this pooled analysis suggest that increased HNC risks observed with earlier age at starting tobacco smoking are largely due to longer duration and higher cumulative tobacco exposures.

Incense burning is common worldwide and produces environmental toxicants that may influence health; however, biologic effects have been little studied. In 303 Emirati adults, we tested the hypothesis that incense use is linked to compositional changes in the oral microbiota that can be potentially significant for health. The oral microbiota was assessed by amplification of the bacterial 16S rRNA gene from mouthwash samples. Frequency of incense use was ascertained through a questionnaire and examined in relation to overall oral microbiota composition (PERMANOVA analysis), and to specific taxon abundances, by negative binomial generalized linear models. We found that exposure to incense burning was associated with higher microbial diversity (p < 0.013) and overall microbial compositional changes (PERMANOVA, p = 0.003). Our study also revealed that incense use was associated with significant changes in bacterial abundances (i.e. depletion of the dominant taxon Streptococcus), even in occasional users (once/week or less) implying that incense use impacts the oral microbiota even at low exposure levels. In summary, this first study suggests that incense burning alters the oral microbiota, potentially serving as an early biomarker of incense-related toxicities and related health consequences. Although a common indoor air pollutant, guidelines for control of incense use have yet to be developed.

BACKGROUND & AIMS/OBJECTIVE:Red and processed meat intake is associated with colorectal cancer (CRC) incidence, but it is not clear if intake is associated with patient survival after diagnosis. METHODS:We pooled data from 7627 patients with stage I-IV CRC from 10 studies in the International Survival Analysis in Colorectal Cancer Consortium. Cox proportional hazards regression models were used to evaluate the associations of intake of red and processed meat before diagnosis with overall and CRC-specific survival. RESULTS:Among 7627 patients with CRC, 2338 died, including 1576 from CRC, over a median follow-up time of 5.1 years. In multivariable-adjusted analyses, higher intake of red or processed meat was not associated with overall survival of patients with stage I-III CRC: Q4 vs Q1 red meat hazard ratio [HR], 1.08 (95% CI, 0.93-1.26) and Q4 vs Q1 processed meat HR, 1.10 (95% CI, 0.93-1.32) or with CRC-specific survival: Q4 vs Q1 red meat HR, 1.09 (95% CI, 0.89-1.33) and Q4 vs Q1 processed meat HR, 1.11 (95% CI, 0.87-1.42). Results were similar for patients with stage IV CRC. However, patients with stage I-III CRC who reported an intake of processed meat above the study-specific medians had a higher risk of death from any cause (HR, 1.12; 95% CI, 1.01-1.25) than patients who reported eating at or less than the median. CONCLUSION/CONCLUSIONS:In this large consortium of CRC patient cohorts, intake of red and processed meat before a diagnosis of CRC was not associated with shorter survival time after diagnosis, although a possible weak adverse association cannot be excluded. Studies that evaluate dietary data from several time points before and after cancer diagnosis are required to confirm these findings.