Background: Telomeres protect from DNA degradation and maintain chromosomal stability. Short telomeres have been associated with an increased risk of cancer at several sites. However, there is limited knowledge about the lifestyle determinants of telomere length. We aimed to determine the effect of three factors, known to be important in cancer etiology, on relative leukocyte telomere length (rLTL): alcohol consumption, smoking, and physical activity.Methods: This cross-sectional study included 477 healthy volunteers ages 20 to 50 years who completed a questionnaire and provided a fasting blood sample. Multiplex quantitative realtime PCR (qPCR) was used to measure rLTL. Regression coefficients were calculated using multiple linear regression while controlling for important covariates.Results: There was no association between alcohol consumption and rLTL. Daily smokers and those in the middle and lower

Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced when meat is cooked at high temperatures, is an emerging risk factor for colorectal cancer (CRC). In a cross-sectional study of 342 patients undergoing a screening colonoscopy, the role of 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), the three most abundant HAAs found in cooked meats, and total mutagenic activity in cooked meats were examined in relation to colorectal adenoma risk. Given that genetic differences in the ability to biotransform HAAs and repair DNA are postulated to modify the HAA-CRC relationship, gene-diet interactions were also examined. Among the total study population, no relationships were observed between dietary HAAs or meat mutagenicity, and colorectal adenoma risk; however, in males, positive associations between dietary HAAs/meat mutagenicity exposures and adenoma risk were suggestive of a relationship. In a separate analysis, polymorphisms in CYP1B1 were found to be associated with colorectal adenoma risk. Additionally, gene-diet interactions were observed for dietary PhIP and polymorphisms in CYP1B1 and XPD, dietary DiMeIQx and XPD polymorphisms, and meat mutagenicity exposure and CYP1B1 polymorphisms. Overall, increased colorectal adenoma risk was observed with higher HAA/meat mutagenicity exposures among those with polymorphisms which confer greater activity to biotransform HAAs and/or lower ability to repair DNA. This research supports the link between dietary HAAs and genetic susceptibility in colorectal adenoma etiology. The vast majority of CRCs arise from colorectal adenomas; thus, the results of this study suggest that changes in meat preparation practices limiting the production of HAAs may be beneficial for CRC prevention.

Telomere length has been associated with risk of several cancers. However, studies of the relationship between telomere length and colorectal cancer risk have been inconsistent. This study examined the relationship between telomere length in normal colon tissue and the prevalence of colorectal adenoma, a precursor to colorectal cancer. This nested case-control study consisted of 85 patients aged 40 to 65 undergoing a screening colonoscopy: 40 cases with adenoma(s) detected at colonoscopy and 45 controls with normal colonoscopy. During the colonoscopy, two pinch biopsies of healthy, normal appearing mucosa were obtained from the descending colon. Relative telomere length (rTL) was quantified in DNA extracted from colon mucosa using quantitative real-time PCR. Logistic regression was used to assess the relationship between telomere length and adenoma prevalence and estimate odds ratios and 95% confidence intervals. rTL was significantly longer in colon tissue of individuals with adenomas compared to healthy individuals (p = 0.008). When rTL was categorized into quartiles according to the distribution of rTL among controls, individuals with the longest telomeres had increased odds of adenoma when compared to individuals with shortest telomeres (OR = 4.58, 95% CI: 1.19, 17.7). This study suggests that long telomeres in normal colon tissue are associated with increased colorectal cancer risk.

No abstract

Heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, are an emerging biologic explanation for the meat-colorectal cancer relationship. HAAs form DNA adducts; left unrepaired, adducts can induce mutations, which may initiate/promote carcinogenesis. The purpose of this research was to investigate the relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct levels. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood measured using (32)P-postlabeling among 99 healthy volunteers. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. No main effects of dietary HAAs on bulky DNA adduct levels was found. However, those with the putative NAT1 rapid acetylator phenotype had lower adduct levels than those with the slow acetylator phenotype (P = 0.02). Furthermore, having five or more 'at-risk' genotypes was associated with higher bulky DNA adduct levels (P = 0.03). Gene-diet interactions were observed between NAT1 polymorphisms and dietary HAAs (P < 0.05); among the slow acetylator phenotype, higher intakes of HAAs were associated with an increase in DNA adduct levels compared to lower intakes. This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. However, the lack of a strong main effect of HAAs suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this population; future studies should consider relevant gene-diet interactions to clarify the role of HAAs in carcinogenesis.

Among genetically susceptible individuals, higher bulky DNA adducts in the colon was associated with the prevalence of colorectal adenomas. The inverse correlation between blood and colon tissue measures demonstrates the importance of quantifying biomarkers in target tissues.

Background: There is compelling evidence to suggest that aspects of diet influence cancer risk; specifically, high meat consumption is associated with elevated risks. Exposure to heterocyclic aromatic amines (HAAs), carcinogens produced in meat when cooked at high temperatures, is a hypothesized explanation for the meat-cancer relationship. Reactive HAA metabolites form adducts with DNA; left unrepaired, adducts can induce mutations which may initiate/promote carcinogenesis. Genetic differences in the ability to biotransform HAAs (as conferred by polymorphisms in CYP1A1, CYP1A2, CYP1B1, NAT1 and NAT2) and repair DNA adducts (as conferred by polymorphisms in XPA, XPD and XRCC1) is postulated to modify the dietary HAAs-DNA adduct relationship. Methods: In a cross-sectional study of 99 healthy volunteers recruited from Kingston, Ontario, Canada, dietary exposure to HAAs and bulky DNA adduct levels in blood leukocytes was investigated. A detailed questionnaire was used in combination with a mutagen database to estimate average intake of dietary HAAs. Specifically, the detailed questionnaire obtained the average frequency of consumption, usual level of doneness and usual serving size of nine commonly consumed meats items with high HAA content. Bulky DNA adduct levels were measured in blood collected after an overnight fast using 32P-postlabelling. Least squares regression was used to examine the relationship between dietary HAA exposure and bulky DNA adduct levels in blood. Gene-diet interactions between dietary HAAs and genetic factors relevant to the biotransformation of HAAs and DNA repair were also examined. Results: No main effects of dietary exposure to HAAs on bulky DNA adduct levels were observed. However, polymorphisms in NAT1 were found to associate with bulky DNA adduct levels. Specifically, those with the putative NAT1*10 rapid acetylator phenotype had a lower adduct level than those with the slow acetylator phenotype (p=0.02). Furthermore, having five or more ‘at-risk’ genotypes was associated with higher bulky DNA adduct levels (p=0.03). Gene-diet interactions were also observed between the NAT1*10 allele and dietary HAAs (p&lt;0.05); specifically, among the slow acetylator phenotype, higher intakes of dietary HAAs were associated with an increase in DNA adduct levels compared to lower intakes. Conclusions: This study provides evidence of a biologic relationship between dietary HAAs, genetic susceptibility and bulky DNA adduct formation. The lack of a strong independent association between dietary HAAs and DNA adducts suggests that dietary HAAs are not a large contributor to bulky DNA adducts in this Canadian population; future studies should consider relevant gene-diet interactions to clarify the potential role of HAAs in carcinogenesis. Citation Format: Vikki Ho, Sarah Peacock, Thomas E. Massey, Roger W. L. Godschalk, Frederik-Jan van Schooten, Jian Chen, Will D. King. Exposure to heterocyclic aromatic amines, genetic susceptibility and bulky DNA adduct levels in blood leukocytes. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A10.