Biomedical subjects

Rashmi Sinha

Publications and source records attributed to Rashmi Sinha.

18 recordsLinked to original sources

PubMed2026

Fecal immunochemical tests from population-based colorectal cancer screening programs support prospective microbiome cohorts.

BACKGROUND: Large, prospective cohorts are needed to research the gut microbiome's role in colorectal cancer (CRC) risk. We evaluated the gut microbiome leveraging residual fecal immunochemical tests (FIT) from a CRC screening program in Turin, Italy, and conducted one of the largest population-based case-control studies across the adenoma-carcinoma sequence to date. METHODS: We extracted DNA from residual FIT stool, used whole-genome shotgun sequencing, and included those with CRC (N = 44), advanced adenomas (N = 269), early adenomas (N = 134), and FIT-negative controls (N = 478). Alpha diversity, beta diversity, and species, gene, and pathway relative abundances were estimated. Multivariable logistic regression models were used to estimate associations of these metrics with colorectal neoplasms. RESULTS: Alpha diversity was mostly inversely associated with colorectal neoplasms, particularly early adenomas (OR: 0.45, 95% CI: 0.25-0.80; P = 0.01). Presence of oral pathogens, including Parvimonas micra, was associated with higher odds of CRC. Furthermore, Escherichia coli and Bacteroides fragilis were strongly associated with higher odds of all colorectal neoplasms. Several genes and pathways were associated with colorectal neoplasms. CONCLUSIONS: Our findings align with smaller studies of the gut microbiome and colorectal neoplasms, supporting that CRC screening programs provide opportunities to prospectively study the gut microbiome's association with cancer risk in large populations.

Humans↗

PubMed2025

Insulinemic and inflammatory dietary patterns and colorectal cancer risk: a dietary data harmonization study of one million participants in the Consortium of Metabolomics Studies (COMETS).

BACKGROUND: Inflammatory and insulinemic dietary patterns have been associated with colorectal cancer (CRC) risk, but generalizability across diverse populations with heterogeneous food supplies and dietary behaviors has not been established. OBJECTIVES: We harmonized disparate dietary and covariate data on a large scale to compute the reverse Empirical Dietary Index for Hyperinsulinemia (rEDIH), reverse Empirical Dietary Inflammatory Pattern (rEDIP), and Healthy Eating Index (HEI)-2015 scores, and tested their associations with CRC risk. METHODS: We leveraged data among 501,892 women and 407,390 men from 6 cohorts across the United States (NIH-AARP, Multi-Ethnic Study of Atherosclerosis, Prostate, Lung, Colorectal, and Ovarian, SCCS) and Europe (EPIC, ATBC) with varying sociodemographic characteristics, participating in the Consortium of Metabolomics Studies. We harmonized nomenclature and nutritional information of >800 unique food items across cohorts. We used multivariable-adjusted Cox regression, adjusting for demographic, clinical, and lifestyle factors, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between the dietary indices and CRC risk per cohort, then meta-analyzed the estimates. RESULTS: During a median follow-up of 14.9 y, 16,525 incident CRC cases were diagnosed. Participants in the highest quintile of rEDIH (low-insulinemic diet) had an 18% reduced risk of CRC (HR: 0.82; 95% CI: 0.78, 0.86) compared with those in the lowest quintile. For the same comparison, similar risk reductions were observed for rEDIP (anti-inflammatory diet) (HR: 0.84; 95% CI: 0.80, 0.89) and HEI-2015 (overall dietary quality) (HR: 0.80; 95% CI: 0.76, 0.85). Heterogeneity between cohorts in the meta-analyzed estimates was low for rEDIH (I2 = 22.3%) compared with rEDIP (I2 = 62.5%) and HEI-2015 (I2=83.9%). CONCLUSIONS: Using carefully harmonized data from nearly 1 million individuals in the United States and Europe, we observed significant CRC risk reduction with habitual intake of low-insulinemic and anti-inflammatory dietary patterns, comparable with higher overall dietary quality. Study findings underscore the utility of these dietary patterns for global cancer prevention efforts.

Humans↗

PubMed2025

Animal farming and the oral microbiome in the Agricultural Health Study.

BACKGROUND: Raising farm animals imparts various exposures that may shape the human microbiome. The oral microbiome has been increasingly implicated in disease development. Animal farming has also been associated with certain chronic diseases such as cancer; however, underlying biological mechanisms are unclear. We investigated associations between raising farm animals and the oral microbiome in the Agricultural Health Study. METHODS: This analysis included 1,245 participants (865 farmers and 380 spouses) who provided oral wash specimens and information on types and numbers of specific animals raised on their farms within 2 years before sample collection. The oral microbiome was measured by sequencing the V4 region of the 16S ribosomal RNA gene. We evaluated associations of farm animal exposures with alpha and beta diversity metrics (within- and between-sample diversity, respectively), as well as presence and relative abundance of specific bacterial genera. All analyses adjusted for potential confounders (e.g., age, sex, smoking, alcohol consumption). RESULTS: Overall, 63 % of participants raised farm animals, most commonly cattle (46 %) and hogs (20 %). Those who raised a large number of hogs (≥2,000 vs. no hogs) had higher alpha diversity. Conversely, raising sheep/goats and raising larger numbers of poultry were associated with lower alpha diversity. Beta diversity was not significantly different between participants with and without any farm animals. Participants raising any farm animals had higher relative abundance of Porphyromonas and lower relative abundances of Prevotella and Ruminococcaceae UCG-014. Several genera were more likely to be absent with specific animal exposures (e.g., Capnocytophaga for cattle and sheep/goats; Corynebacterium, Dialister, Stomatobaculum, and Solobacterium for sheep/goats and poultry). CONCLUSIONS: This was the largest study of farm animal exposures and the human microbiome to date. Findings suggest that raising specific farm animals may influence the oral microbiome, supporting the need to further investigate the potential role of animal farming in disease etiology.

Microbiota↗

PubMed2003

Linkage disequilibrium and haplotype analysis between serotonin receptor 1B gene variations and subtypes of alcoholism.

A number of studies have reported a possible association between serotonergic pathway genes and alcoholism. A silent polymorphism (G to C substitution) in the gene encoding the autoreceptor 5-HT1B was linked to antisocial alcoholism in Finnish and an American Indian populations [Lappalainen et al., 1998: Arch Gen Psychiatry 55:989-994]. Several other polymorphisms of this gene have been investigated for their association with neuropsychiatric disorders. In the present study, a sample of 133 alcoholics without and 39 alcoholics with medical complications, and 88 normal controls was screened for three single nucleotide polymorphisms (SNPs), G861C, G261T, and C129T, in the 5-HT1B gene. The goal was to investigate their association with the disease, to measure the strength of linkage disequilibrium (LD) between the SNPs, and to compare haplotype frequencies between alcoholic groups and normal controls. Data was also analyzed on the basis of Type I (n = 47) and Type II (n = 85) alcoholism. There was no significant difference in the allele frequencies or the genotype distribution between any alcoholic groups, alcoholic subgroups, and controls for any polymorphism. G861C and C129T polymorphisms were in complete LD. The pattern of distribution of haplotypes was similar in patients and controls. It is concluded that these SNPs are not playing any direct role in the development of susceptibility to alcoholism in our patient sample.

Alcoholism↗

PubMed2003

Meat, fat, and their subtypes as risk factors for colorectal cancer in a prospective cohort of women.

The authors investigated the association of intakes of meat and fat with colorectal cancer in a prospective cohort of women in the United States. Between 1987 and 1989, 45,496 women completed a 62-item National Cancer Institute/Block food frequency questionnaire, and during 386,716 person-years of follow-up, there were 487 incident cases of colorectal cancer. The authors used Cox proportional hazards regression to estimate relative risks and 95% confidence intervals for total meat, red meat, white meat, processed meat, and well-done meat intakes, as well as for total fat, saturated fat, and unsaturated fat. Relative risks for increasing quintiles of total meat and red meat consumption indicated no association with colorectal cancer (relative risk for high compared with low quintile = 1.10, 95% confidence interval: 0.83, 1.45) for red meat. For total fat, there was also no association with increasing quintiles of consumption (relative risk for high compared with low quintile = 1.14, 95% confidence interval: 0.86, 1.53). Additionally, none of the other subtypes of either meat or fat showed any association with colorectal cancer. This study provided no evidence of an association between either meat or fat (or any of their subtypes) and colorectal cancer incidence, but the authors cannot rule out the possibility of a modest association.

Age Distribution↗

PubMed2003

Dietary fibre and colorectal adenoma in a colorectal cancer early detection programme.

BACKGROUND: Although dietary fibre has been reported to have no association with colorectal adenoma and cancer, in some studies this topic remains controversial. METHODS: We used a 137-item food frequency questionnaire to assess the relation of fibre intake and frequency of colorectal adenoma. The study was done within the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomised controlled trial designed to investigate methods for early detection of cancer. In our analysis, we compared fibre intake of 33971 participants who were sigmoidoscopy-negative for polyps, with 3591 cases with at least one histologically verified adenoma in the distal large bowel (ie, descending colon, sigmoid colon, or rectum). Odds ratios were estimated by logistic regression analysis. FINDINGS: High intakes of dietary fibre were associated with a lower risk of colorectal adenoma, after adjustment for potential dietary and non-dietary risk factors. Participants in the highest quintile of dietary fibre intake had a 27% (95% CI 14-38, p(trend)=0.002) lower risk of adenoma than those in the lowest quintile. The inverse association was strongest for fibre from grains and cereals and from fruits. Risks were similar for advanced and non-advanced adenoma. Risk of rectal adenoma was not significantly associated with fibre intake. INTERPRETATION: Dietary fibre, particularly from grains, cereals, and fruits, was associated with decreased risk of distal colon adenoma.

Adenoma↗

PubMed2003

Functional variation in promoter region of monoamine oxidase A and subtypes of alcoholism: haplotype analysis.

Monoamine oxidase (MAO) is a mitochondrial enzyme involved in the degradation of certain neurotransmitter amines. MAO-A, due to its function in central nervous system, has been one of the important candidate genes involved in the development of neuropsychiatric disorders. A functional polymorphism in the promoter region of the MAO-A gene has been identified. This variation affects the transcriptional efficiency of the gene. To determine the role of this MAO-A functional polymorphism in the development of subtypes of alcoholism, a sample of alcoholics and normal controls were screened with this marker. The allele frequency differences between total alcoholics, Types I and II alcoholics, and normal controls was not significant. Comparison of male alcoholics to male normal controls for the frequencies of two-loci and three-loci haplotypes was statistically significant. After Bonferroni's correction for multiple tests none of the results remained significant at P < 0.05. Our results indicate that MAO-A may play a role in the development of alcoholism but the gene effect is very small.

Alcoholism↗

PubMed2003

Distributed neural activity during object, spatial and integrated processing in humans.

Information about the form and the spatial location of objects is seamlessly integrated during visual perception. We used event-related potentials (ERPs) to explore neural activity related to processing form, location or the combination of both kinds of features. Healthy subjects performed three versions of a 'match-to-sample' task: a two-object task, a two-location task and an integrated object-location task. Responses were quickest and most accurate during the integrated task, slower and less accurate in the two-location task and slowest and least accurate in the two-object task. ERPs locked to the 'sample' stimulus at encoding, and to the 'target' stimulus during feature comparison differentiated between tasks. 'Sample' stimulus ERPs exhibited task-specific posterior cortical involvement in processing distinct visual features. 'Target' stimulus ERPs revealed task-related differences in features associated with frontal lobe mediated attentional processes: an early latency P300 showed increased amplitude during the integrated task. Results from this experiment support the view that distinct neural circuits mediate form vs. location processing and that form-location integration engages both pathways and upregulates frontal-parietal association networks.

Adult↗

PubMed2003

Dietary carotenoids, vegetables, and lung cancer risk in women: the Missouri women's health study (United States).

OBJECTIVE: To examine the effect of specific dietary carotenoids and their primary plant food sources on lung cancer risk in a population-based case-control study of women. METHODS: Data were available for 587 incident primary lung cancer cases and 624 controls frequency matched to cases based on age. A modified version of the 100-item NCI-Block food-frequency questionnaire was used to obtain information concerning usual diet 2-3 years prior to interview. RESULTS: In models adjusted for age, total calorie intake, pack-years of smoking, and education, beta-carotene, beta-cryptoxanthin, lutein + zeaxanthin, and total carotenoid intake were each associated with a significantly lower risk of lung cancer. Several vegetable groups were predictive of lower lung cancer risk, particularly the frequency of total vegetable intake. Individual and total carotenoids were no longer significantly associated with lower lung cancer risk in models adjusted for total vegetable intake. However, total vegetable intake remained significantly inversely associated with risk in models adjusted for total carotenoids. CONCLUSIONS: These results indicate that consumption of a wide variety of vegetables has a greater bearing on lung cancer risk in a population of smoking and nonsmoking women than intake of any specific carotenoid or total carotenoids.

Aged↗

PubMed2002

Highlights of the eighth international conference on carcinogenic/mutagenic N-substituted aryl compounds.

Research in the 20th century initially identified arylamines as causative factors in occupational carcinogenesis, especially bladder cancer, and subsequently identified arylamines as a major class of mutagens/carcinogens in the environment and diet that are potential risk factors in a variety of human cancers. Current research focuses on understanding of mechanisms of arylamine carcinogenesis, such as the role of metabolic processing, DNA adduct formation, and mutagenesis, and learning more about the molecular alterations in carcinomas induced by these compounds. Furthermore, research to identify human exposures, including developing more sensitive methods for analyzing environmental samples and identifying suitable biomarkers are important aspects of contemporary investigations. In addition, better evaluation of the risk of these compounds in human cancer especially with regard to the impact of genetic polymorphisms is a major focus of research in this field. Although current population studies have sometimes been described as equivocal, improved tools for epidemiology, refined human biomonitoring methods and collaborative endeavors to study multiple population groups now provide a better means to ultimately define the role of arylamines in human carcinogenesis. The purpose of the Eighth International Conference on Carcinogenic/Mutagenic N-Substituted Aryl Compounds, held in Washington, DC, 12-14 November 2001, was to explore the current scope of studies on arylamine carcinogenesis among scientists in basic research and epidemiology and to discuss future research priorities. With the intent of providing a view to the current field of research on aromatic amines, this review presents a synopsis of the Proceedings of the Eighth International Conference and highlights the manuscripts contained in this special issue of Mutation Research.

Aminobiphenyl Compounds↗

PubMed2002

Metabolites of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) in human urine after consumption of charbroiled or fried beef.

Heterocyclic amines (HAs) are carcinogenic combustion products formed during the cooking of meat at moderate to high temperatures. PhIP is the most common HA formed in fried, grilled or broiled meat, and is a colon, breast, and prostate carcinogen in rodents. The major metabolites of PhIP detected in human urine are N(2)-OH-PhIP-N(2)-glucuronide, PhIP-N(2)-glucuronide, N(2)-OH-PhIP-N(3)-glucuronide, and 4'-PhIP-sulphate. We have measured the time course of PhIP in untreated and acid- or alkali-hydrolyzed urines from 10 healthy non-smoking subjects ingesting identical amounts of char-broiled beef (containing both HAs and PAHs) for 5 days. The morning after the first day of broiled beef consumption (containing 7.7 micro g PhIP), urinary concentration of PhIP increased 14- to 38-fold above mean prefeed concentration. Following cessation of broiled meat consumption, urinary PhIP declined to near prefeed levels within 48-72 h. The ratio of alkali-labile PhIP metabolites to unmetabolized PhIP varied by 2.7-fold among subjects, ranging from 18:1 to 48:1. In a subsequent study we measured PhIP in acid-hydrolyzed urine from 66 subjects ingesting beef pan-fried at high temperature. A significant correlation (r=0.61, P<0.0001) was observed between the amount of fried meat ingested and concentration of PhIP in urines collected between 0 and 12h after feeding. Other investigators have identified 2-OH-PhIP in acid-hydrolyzed urine from these subjects, and also observed a significant correlation (r=0.52, P<0.0001) with the amount of fried meat ingested. Additional studies have measured PhIP metabolites in subjects consuming their normal (unrestricted) diet. PhIP was detected in acid-hydrolyzed urine from 20 to 50% of these subjects, depending on ethnic group. Taken together, these studies indicate that significant amounts of PhIP are bioavailable from ingestion of fried or char-broiled meats, and that urinary PhIP metabolites reflect recent (12-24h) ingestion. Furthermore, significant interindividual differences in the amounts of urinary PhIP metabolite excreted are observed following ingestion of similar amounts of PhIP. These differences do not correlate with interindividual differences in excretion of urinary pyrene metabolites in the same individuals after ingestion of char-broiled beef, indicating that levels of PhIP and pyrene metabolites in human urine are mediated by compound-specific metabolic factors.

Animals↗

PubMed2002

Analysis of total meat intake and exposure to individual heterocyclic amines in a case-control study of colorectal cancer: contribution of metabolic variation to risk.

A case-control study of colorectal cancer, consisting of 157 cases and 380 controls matched by sex, ethnicity, decade of age and county of residence was performed to explore the associations between environmental exposure, metabolic polymorphisms and cancer risk. Participants were required to provide a blood sample, undergo caffeine phenotyping and complete an in-person interview that evaluated meat consumption, cooking methods and degree of doneness. A color atlas of foods cooked to different degrees of doneness was used to estimate food preparation techniques and food models were used to estimate serving portion sizes. Data was analyzed using a reference database of heterocyclic amine (HCA) exposure based on the food preferences chosen from the atlas. Data regarding individual food items cooked to different levels of doneness, as well as summary variables of foods and of food groups cooked to different degrees of doneness were also evaluated in a univariate analysis for association with colorectal cancer case status. Three measures of metabolic variation, hGSTA1 genotype, SULT1A1 genotype and the phenotype for CYP2A6 were also evaluated for possible association with colon cancer. While higher exposure to HCAs was strongly associated with colorectal cancer risk, increased consumption of five red meats cooked well done or very well done produced comparable odds ratios (OR) for colorectal cancer risk (OR=4.36, 95% CI 2.08-9.60) for the highest quartile of exposure. Similarly, individuals in the most rapid CYP2A6 phenotype quartile showed an odds ratio (OR = 4.18, 95% CI 2.03-8.90). The ORs for the low activity hGSTA1 and low activity SULT1A1 alleles were 2.0, 95% CI 1.0-3.7 and 0.6, 95% CI 0.3-1.1, respectively. Individual measures of specific HCAs provided little improvement in risk assessment over the measure of meat consumption, suggesting that exposure to other environmental or dietary carcinogens such as nitrosamines or undefined HCAs may contribute to colorectal cancer risk.

Adult↗

PubMed2002

An epidemiologic approach to studying heterocyclic amines.

Diets containing substantial amounts of red meat may increase the risk of colorectal, pancreatic, breast, prostate, and renal cancer. The association with red meat intake may be due to a combination of factors, such as content of fat, protein, and iron, and/or meat preparation (e.g. cooking or preserving methods). Laboratory results have shown that meats cooked at high temperatures contain heterocyclic amines (HCAs) known to be mutagenic and carcinogenic in animals. Many older epidemiologic studies of colon cancer using surrogates for HCA exposure from meat (for example, doneness level, surface browning, frying, intake of gravy) have produced suggestive but inconsistent results. These discrepancies may have resulted in part from having used dietary questionnaires that combined meat-cooking practices in ways that made the intake of HCAs difficult to estimate. Thus, over the last decade we have taken a multidisciplinary approach to investigating whether the association with red meat intake can be explained by meat-cooking practices that produce mutagens/carcinogens. To estimate intake, a database for HCAs have been developed and used in conjunction with a validated meat-cooking food frequency questionnaire (FFQ). To develop biological markers of internal exposure, a metabolic study was conducted where subjects consumed controlled amounts of meat cooked at low and high temperatures. The role of meat type, cooking methods, doneness levels, and meat-cooking mutagens were examined in case-control studies of colorectal adenomas, lung, and breast cancers using both questionnaire information and biomarkers. In a case-control study of colorectal adenomas, an increased risk was associated with a high intake of red meat. Most of this risk was due to intake of red meat cooked until well/very well done and/or by high-temperature cooking techniques such as grilling. Linking the FFQ information to HCA database, the impact several HCAs on risk was evaluated. An increased risk was associated with higher intake of MeIQx, possibly PhIP. Red meat, especially fried and/or well-done red meat, was associated with increased risk of lung cancer in a population-based case-control study. In addition, an increase in risk was demonstrated among non-smokers and moderate smokers for MeIQx intake. In a case-control study of breast cancer well-done red meat and PhIP was associated with increased risk of breast cancer. In this manuscript I will provide one approach to studying the relation of meat cooking-mutagens and cancer risk and will suggest the types of studies that may be required in the future to clarify these associations.

Amines↗

PubMed2002

Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii.

Heterocyclic amines (HAAs) and polycyclic hydrocarbons are suspected colorectal cancer (CRC) carcinogens that are found in well-done meat. They require metabolic activation by phase I enzymes, such as the smoking-inducible CYP1A isoenzymes. N-acetyltransferase 2 (NAT2) also play a role in the further activation of HAAs. We conducted a population-based case-control study in Hawaii to test the associations of preference for well-done red meat and HAA intake with colon and rectal cancers, as well as the modifying effects of NAT2 and CYP1A2. We interviewed 727 Japanese, Caucasian or Native Hawaiian cases and 727 controls matched on sex, age, and ethnicity. HAA intake was estimated based on consumption of meat and fish for each of several cooking methods and doneness levels. A subgroup of 349 cases and 467 controls was phenotyped for CYP1A2 by a caffeine test. We found that preference for well-done red meat was associated with a 8.8-fold increased risk of CRC (95% CI: 1.7-44.9) among ever-smokers with the NAT2 and CYP1A2 rapid phenotypes, compared to ever-smokers with low NAT2 and CYP1A2 activities and who preferred their red meat rare or medium. A dose-dependent association was also found between the HAA intake estimates and male rectal cancer, with a two- to three-fold increase in risk from the low (T(1)) to high (T(3)) tertile of intake for each HAA. This association was strongest for MeIQx. HAA intake was not associated with male colon cancer or colon or rectal cancer in women. These data provide support to the hypothesis that exposure to pyrolysis products through consumption of well-done meat increases the risk of CRC, particularly in individuals who smoke and are genetically susceptible (as determined by a rapid phenotype for both NAT2 and CYP1A2). An attempt to examine the risk associated with specific HAAs suggested that the main HAAs increase risk of rectal cancer in men and that they do not appreciably affect risk of rectal cancer in women or of colon cancer in either sex.

Adolescent↗

PubMed2002

Meat intake and cooking techniques: associations with pancreatic cancer.

Heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs), formed in temperature and time-dependent manners during cooking of meat, may increase the risk of certain cancers. As these compounds could be carcinogenic for the pancreas, we assessed meat intake, preparation methods, and doneness preferences as risk factors for exocrine pancreatic cancer. In a case-control study (cases=193, controls=674), subjects provided information on their usual meat intake and how it was cooked, e.g. fried, grilled or barbecued (BBQ), etc. Meat doneness preferences were measured using photographs that showed internal doneness and external brownness with a numerical scale. Data were analyzed with unconditional logistic regression. Odds ratios (ORs) increased with increased intake of grilled/BBQ red meat in an analysis adjusted for age, sex, smoking, education, race, and diabetes. Based on amount of BBQ meat consumed, the OR and 95% confidence interval (CI) for the fifth quintile relative to the reference group (quintiles 1 and 2) was 2.19 (1.4, 3.4). Findings were not substantively changed by further adjustment for calories, total fat, fruit and vegetables, or alcohol consumption (from a food frequency questionnaire (FFQ)). Other meat variables did not show statistically significant associations with risk nor did they substantively alter the findings for BBQ. These included total meat, processed meat, total red meat, total white meat, total broiled meat, total fried meat, or total meat cooked by means other than grilling. We conclude that grilled red meat intake is a risk factor for pancreatic cancer and that method of meat preparation in addition to total intake is important in assessing the effects of meat consumption in epidemiologic studies.

Adult↗

PubMed2002

Association of prostate cancer with rapid N-acetyltransferase 1 (NAT1*10) in combination with slow N-acetyltransferase 2 acetylator genotypes in a pilot case-control study.

N-acetyltransferase-1 (NAT1) and N-acetyltransferase-2 (NAT2) are important in the metabolism of aromatic and heterocyclic amine carcinogens that induce prostate tumors in the rat. We investigated the association of genetic polymorphisms in NAT1 and NAT2, alone and in combination, with human prostate cancer. Incident prostate cancer cases and controls in a hospital-based case-control study were frequency-matched for age, race, and referral pattern. The frequency of slow acetylator NAT1 genotypes (NAT1*14, *15, *17) was 5.8% in controls but absent in cases. In contrast, in comparison with all other NAT1 genotypes the putative rapid acetylator NAT1 genotype (NAT1*10) was significantly higher in prostate cancer cases than controls (OR, 2.17; 95% CI, 1.08-4.33; P = 0.03). Combinations of NAT1*10 with NAT2 slow acetylator genotypes (OR, 5.08; 95% CI, 1.56-16.5; P = 0.008) or with NAT2 very slow (homozygous NAT2*5) acetylator genotypes (OR, 7.50; 95% CI, 1.55-15.4; P = 0.016) further increased prostate cancer risk. The results of this small pilot study suggest increased susceptibility to prostate cancer for subjects with combinations of NAT1*10 and slow (particularly very slow) NAT2 acetylator genotypes. This finding should be investigated further in larger cohorts and in other ethnic populations.

Aged↗

PubMed2002

Highly sensitive chemiluminescence immunoassay for benzo[a]pyrene-DNA adducts: validation by comparison with other methods, and use in human biomonitoring.

A chemiluminescence immunoassay (CIA) utilizing antiserum elicited against DNA modified with (+/-)-7beta, 8alpha-dihydroxy-9alpha,10alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]- pyrene (BPDE) has been developed and validated to study the formation of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in human tissues. Advantages include a low limit of detection for 10b-(deoxyguanosin-N(2)-yl)-7beta,8alpha,9alpha-trihydroxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG, approximately 1.5 adducts/10(9) nucleotides using 20 micro g DNA) and a high signal-to-noise ratio (> or =100). The CIA BPDE-DNA standard curve gave 50% inhibition at 0.60 +/- 0.08 fmol BPdG (mean +/- SE, n = 30), which was a 10-fold increase in sensitivity compared with the dissociation-enhanced lanthanide fluoroimmunoassay (DELFIA). Calf thymus DNA modified with [1,3-(3)H]BPDE was assayed by radiolabeling, (32)P-postlabeling, DELFIA and CIA, and all assays gave similar values. Liver DNAs from mice exposed to 0.5 and 1.0 mg [7,8-(3)H]benzo[a]pyrene (BP) were assayed by the same four assays and a dose-response was obtained with all assays. The BPDE-DNA CIA was further validated in MCL-5 cells exposed to 4 micro M BP for 24 h, where nuclear and mitochondrial DNA adduct levels were associated with an increase in DNA tail length measured by the Comet assay. Human peripheral blood cell (buffy coat) DNA samples (n = 43) obtained from 25 individuals who were either colorectal adenocarcinoma patients or controls were assayed by BPDE-DNA CIA. Three samples (7%) were non-detectable, and the remaining 40 samples had values between 0.71 and 2.21 PAH-DNA adducts/10(8) nucleotides. The intra-assay coefficient of variation (CV), for four wells on the same microtiter plate, was 1.85%. Sufficient DNA for two assays, on separate plates, was available for 38 of the 43 samples, and the PAH-DNA adduct values obtained were highly correlated (r(2) = 0.95). Coded duplicate DNA samples from 15 individuals were assayed four times gave an inter-assay CV of 13.8%.

Adenocarcinoma↗

PubMed2002

Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas.

High red meat intake has been linked with an increased risk of colorectal cancer and adenomas. During high temperature cooking of red meats, heterocyclic amines (HCAs) are generated; however, to be carcinogenic, they must be metabolized by enzymes including cytochrome P450 1A2 (CYP1A2) and N-acetyltransferase 1 (NAT1) and/or N-acetyltransferase 2 (NAT2). We have conducted a clinic-based case-control study of colorectal adenomas that focused on assessment of exposure to HCAs (estimated by use of a HCA database and meat cooking module) and modification of these exposures by genetic factors. We have previously reported that intake of MeIQx was associated with an increased risk of colorectal adenomas [overall association at 80th percentile, > 27.00 ng/day: odds ratio (OR) = 2.68, 95% confidence interval (CI) 1.58-4.55]. Here, we report our evaluation of whether variation in CYP1A2, NAT1 and/or NAT2 modify the association between HCAs and colorectal adenoma formation in 146 cases and 228 frequency-matched controls. The NAT1*10 allele was associated with a nonsignificant increased risk of colorectal adenomas (OR = 1.43; 95% CI 0.86-2.36). Further, when we analysed 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) intake as a categorical variable, we observed a six-fold increase in adenoma risk among rapid NAT1 acetylators who consumed more than 27 ng a day (OR = 6.50; 95% CI 2.16-19.7), whereas among slow NAT1 acetylators, the increase in risk was two-fold (OR = 2.32; 95% CI 1.12-4.81). While suggestive, the results were not significantly different from each other on either an additive or multiplicative scale. In contrast, NAT2 genotype and CYP1A2 and NAT2 hepatic activity measured by caffeine urinary metabolites were not associated with adenoma risk, although an increase in risk with rapid CYP1A2 activity could not be ruled out (OR = 1.46; 95% CI 0.76-2.81). Moreover, there was no evidence that the effect of MeIQx was enhanced among subjects in any subgroup defined by variation in these measures. These results are compatible with the hypothesis that high HCA exposure is associated with an increased risk of colorectal adenomas, particularly in genetically susceptible subgroups. Further study of larger populations is needed to confirm and extend these observations.

Adenoma↗