Vitamin B6 catabolism and lung cancer risk: results from the Lung Cancer Cohort Consortium (LC3).

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Indoor concentrations of nitrogen dioxide and sulfur dioxide from burning solid fuels for cooking and heating in Yunnan Province, China.

The Chinese national pollution census has indicated that the domestic burning of solid fuels is an important contributor to nitrogen dioxide (NO2 ) and sulfur dioxide (SO2 ) emissions in China. To characterize indoor NO2 and SO2 air concentrations in relation to solid fuel use and stove ventilation in the rural counties of Xuanwei and Fuyuan, in Yunnan Province, China, which have among the highest lung cancer rates in the nation, a total of 163 participants in 30 selected villages were enrolled. Indoor 24-h NO2 and SO2 samples were collected in each household over two consecutive days. Compared to smoky coal, smokeless coal use was associated with higher NO2 concentrations [geometric mean (GM) = 132 µg/m(3) for smokeless coal and 111 µg/m(3) for smoky coal, P = 0.065] and SO2 [limit of detection = 24 µg/m(3) ; percentage detected (%Detect) = 86% for smokeless coal and 40% for smoky coal, P < 0.001]. Among smoky coal users, significant variation of NO2 and SO2 air concentrations was observed across different stove designs and smoky coal sources in both counties. Model construction indicated that the measurements of both pollutants were influenced by stove design. This exposure assessment study has identified high levels of NO2 and SO2 as a result of burning solid fuels for cooking and heating.

Circulating levels of immune and inflammatory markers and long versus short survival in early-stage lung cancer.

BACKGROUND: Some patients diagnosed with early-stage lung cancer and treated according to standard care survive for only a short period of time, while others survive for years for reasons that are not well understood. Associations between markers of inflammation and survival from lung cancer have been observed. MATERIALS AND METHODS: Here, we investigate whether circulating levels of 77 inflammatory markers are associated with long versus short survival in stage I and II lung cancer. Patients who had survived either <79 weeks (~1.5 years) (short survivors, SS) or >156 weeks (3 years) (long survivors, LS) were selected from a retrospective population-based study. Logistic regression was used to calculate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The false discovery rate was calculated to adjust for multiple testing. RESULTS: A total of 157 LS and 84 SS were included in this analysis. Thirteen markers had adjusted OR on the order of 2- to 5-fold when comparing the upper and lower quartiles with regard to the odds of short survival versus long. Chemokine CCL15 [chemokine (C-C motif) ligand 15] was the most significant marker associated with increased odds of short survival (ORs = 4.93; 95% CI 1.90-12.8; q-value: 0.042). Smoking and chronic obstructive pulmonary disease were not associated with marker levels. CONCLUSIONS: Our results provide some evidence that deregulation of inflammatory responses may play a role in the survival of early-stage lung cancer. These findings will require confirmation in future studies.

Plasma levels of dioxins, furans, non-ortho-PCBs, and TEQs in the Seveso population 17 years after the accident.

BACKGROUND: The Seveso accident (Italy) in 1976 caused the contamination of a large population by 2,3,7,8-tetrachlorodibenzo-para-dioxin (2,3, 7,8-TCDD). The contaminated territory was divided into three zones: A (very high contamination), B (high contamination), and R (low contamination). We report here the plasma concentrations of seven polychlorinated dibenzo-para-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), four non-ortho-polychlorinated biphenyls PCBs (nPCBs), and Toxic Equivalencies (TEQs) in a sample of residents in the most polluted zones A and B and in a reference non-contaminated zone. METHODS: From December 1992 to March 1994, 62 individuals were randomly selected from the population living in zone A (No. =7) and B (No. =55). A sample of 59 subjects living in a surrounding non-contaminated area (non-ABR), frequency-matched by gender, age, and smoking history, was used as reference. All subjects were administered a questionnaire surveying demographic, lifestyle, medical history, and accident-related factors. We assayed plasma PCDD, PCDF, and nPCB concentrations by high-resolution gas chromatography/high resolution mass spectrometric (HRGC/HRMS) analysis, with results reported as pg/g of lipid, or parts per trillion (ppt). We calculated TEQs using the WHO 2005 Toxic Equivalency Factors (TEFs). RESULTS: We found elevated median levels of 2,3, 7,8-TCDD in plasma samples of subjects living in zone A (73.3 ppt) and zone B (12.4 ppt), compared with residents in the reference zone (5.5 ppt). In analyses adjusted for gender, age, smoking, and body mass index (BMI), none of the other congeners showed levels higher than reference in the contaminated zones. Compared with men, women showed higher levels (113%) of 2,3, 7,8-TCDD and a slight elevation (17%) of TEQ for the other congeners. Age was strongly positively associated with most congener levels; TEQs for PCDDs, PCDFs, and nPCBs showed respectively 12%, 24%, and 41% increases for every 10 years of age. Current smokers had lower (from -37% to -67%) TEQ levels than subjects who had never smoked. BMI was negatively associated with levels of a few congeners, but with no impact on TEQ values. CONCLUSIONS: The Seveso accident caused a severe exposure of the population to 2,3,7,8-TCDD only. None of the other congeners analyzed showed variation across zones. Age showed a strong positive association with TEQs for all classes of compounds (PCDDs, PCDFs, and nPCBs).

Epstein-Barr virus microRNAs and lung cancer.

BACKGROUND: We conducted the first analysis of viral microRNAs (miRNAs) in lung cancer, with a focus on Epstein-Barr virus (EBV). METHODS: We evaluated viral miRs with a two-channel oligo-array targeting mature, anti-sense miRNAs in 290 cases. In 48 cases, we compared microarray and real-time quantitative PCR (qPCR) expression for three EBV miRNAs. We tested for EBV DNA, RNA, and protein in tumour tissue from six cases with and six cases without strong qPCR-based evidence of EBV miRNAs. RESULTS: The EBV miRNAs strongly differentiated between adenocarcinoma and squamous cell carcinoma using the microarray (P<0.01 for 9 out of 16 EBV miRNAs). However, microarray and qPCR measurements of BART1, BART2, and BHRF1-3 expression were not significantly correlated (P=0.53, 0.94, and 0.47, respectively). Although qPCR provided substantial evidence of EBV miRNAs in 7 out of 48 cases, only 1 of these 7 cases had detectable EBV DNA in tumour tissue. None had detectable EBV RNA or protein by histochemical stains. CONCLUSION: In a comprehensive evaluation of EBV miRNA, DNA, RNA, and protein in lung cancer, we found little evidence of EBV in lung tumour tissue. Discrepancies between microarray- and qPCR-based strategies highlight the difficulty of validating molecular markers of disease. Our results do not support a role of EBV in lung cancer.

Differential effects of smoking on lung cancer mortality before and after household stove improvement in Xuanwei, China.

BACKGROUND: In Xuanwei County, Yunnan Province, China, lung cancer mortality rates in both males and females are among the highest in China. METHODS: We evaluated differential effects of smoking on lung cancer mortality before and after household stove improvement with chimney to reduce exposure to smoky coal emissions in the unique cohort in Xuanwei, China. Effects of independent variables on lung cancer mortality were measured as hazard ratios and 95% confidence intervals using a multivariable Cox regression model that included separate time-dependent variables for smoking duration (years) before and after stove improvement. RESULTS AND CONCLUSION: We found that the effect of smoking on lung cancer risk becomes considerably stronger after chimney installation and consequent reduction of indoor coal smoke exposure.

Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival.

BACKGROUND: MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression. METHODS: we analysed 12 SNPs in POLR2A, RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t-tests and global permutation tests. RESULTS: a haplotype in RNASEN (Drosha) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19-2.92, P=0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression (P=0.013) and with miR expression changes (global P=0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a). CONCLUSION: inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival.

Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates?

Observational epidemiological studies often include prevalent cases recruited at various times past diagnosis. This left truncation can be dealt with in non-parametric (Kaplan-Meier) and semi-parametric (Cox) time-to-event analyses, theoretically generating an unbiased hazard ratio (HR) when the proportional hazards (PH) assumption holds. However, concern remains that inclusion of prevalent cases in survival analysis results inevitably in HR bias. We used data on three well-established breast cancer prognosticators - clinical stage, histopathological grade and oestrogen receptor (ER) status - from the SEARCH study, a population-based study including 4470 invasive breast cancer cases (incident and prevalent), to evaluate empirically the effectiveness of allowing for left truncation in limiting HR bias. We found that HRs of prognostic factors changed over time and used extended Cox models incorporating time-dependent covariates. When comparing Cox models restricted to subjects ascertained within six months of diagnosis (incident cases) to models based on the full data set allowing for left truncation, we found no difference in parameter estimates (P=0.90, 0.32 and 0.95, for stage, grade and ER status respectively). Our results show that use of prevalent cases in an observational epidemiological study of breast cancer does not bias the HR in a left truncation Cox survival analysis, provided the PH assumption holds true.

Lung cancer and the debrisoquine metabolic phenotype.

In a case-control study, we tested the hypothesis that the genetically determined ability to metabolize debrisoquine is related to risk of lung cancer. Overall, individuals who were extensive metabolizers of debrisoquine were at significantly greater risk of lung cancer than those who were poor or intermediate metabolizers (odds ratio = 6.1; 95% confidence interval = 2.2-17.1). In this study, case patients had lung cancer, and control subjects had either chronic obstructive pulmonary disease or cancers other than lung cancer. Results were adjusted for age, race, asbestos exposure, and smoking. Both black and white individuals who were extensive metabolizers of debrisoquine were at significantly increased risk after similar adjustment (for blacks, odds ratio = 4.5, 95% confidence interval = 1.1-18.1; for whites, odds ratio = 10.2, 95% confidence interval = 2.0-51.4). Significantly increased risk of lung cancer was also present for individuals who were extensive metabolizers when subjects with chronic obstructive pulmonary disease or other cancers were considered separately. These data confirm that the ability to metabolize debrisoquine is a major determinant of susceptibility to lung cancer. Evaluation of the marker in other case-control settings, further exploration of racial differences, and the prospective evaluation of this marker in subgroups at high risk of lung cancer are areas worthy of further study.

Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers.

BACKGROUND: The consumption of alcoholic beverages is a strong risk factor for cancers of the oral cavity and pharynx (oral cancers). Alcohol dehydrogenase type 3 (ADH3) metabolizes ethanol to acetaldehyde, a carcinogen. We evaluated whether individuals homozygous for the fast-metabolizing ADH3(1) allele (ADH3[1-1]) have a greater risk of developing oral cancer in the presence of alcoholic beverage consumption than those with the slow-metabolizing ADH3(2) allele (ADH3[1-2] and ADH3[2-2]). METHODS: As part of a population-based study of oral cancer conducted in Puerto Rico, the ADH3 genotypes of 137 patients with histologically confirmed oral cancer and of 146 control subjects (i.e., individuals with no history of oral cancer) were determined by molecular genetic analysis of oral epithelial cell samples. Risks were estimated by use of multiple logistic regression analyses. RESULTS: Compared with nondrinkers with the ADH3(1-1) genotype, consumers of at least 57 alcoholic drinks per week with the ADH3(1-1), ADH3(1-2), and ADH3(2-2) genotypes had 40.1-fold (95% confidence interval [CI] = 5.4-296.0), 7.0-fold (95% CI = 1.4-35.0), and 4.4-fold (95% CI = 0.6-33.0) increased risks of oral cancer, respectively; the risk associated with the ADH3(1-1) genotype, compared with the ADH3(1-2) and ADH3(2-2) genotypes combined, was 5.3 (95% CI = 1.0-28.8) among such drinkers. Considering all levels of alcohol consumption, the risk of oral cancer per additional alcoholic drink per week increased 3.6% (95% CI = 1.9%-5.4%) for subjects with the ADH3(1-1) genotype and 2.0% (95% CI = 0.9%-3.0%) for subjects with the ADH3(1-2) or ADH3(2-2) genotype (two-sided P = .04). CONCLUSIONS: The ADH3(1-1) genotype appears to substantially increase the risk of ethanol-related oral cancer, thus providing further evidence for the carcinogenicity of acetaldehyde.

CYP2E1 genetic polymorphisms and risk of nasopharyngeal carcinoma in Taiwan.

BACKGROUND: Nasopharyngeal carcinoma occurs disproportionately among individuals of Chinese descent. The cytochrome P450 2E1 enzyme (CYP2E1) is known to activate nitrosamines and other carcinogens that are possibly involved in the development of this disease. Certain alleles of the CYP2E1 gene are thought to be more highly expressed than others, and their distribution varies between Asian and Caucasian populations. We conducted a case-control study to investigate whether such variations affect the risk of developing nasopharyngeal cancer. METHODS: Three hundred sixty-four patients with nasopharyngeal carcinoma (96% of 378 eligible patients) and 320 control subjects (86% of 374 eligible subjects) were studied. A risk factor questionnaire was administered to participants to assess factors postulated to be linked to nasopharyngeal carcinoma. Peripheral blood was obtained from all subjects and DNA was purified from nucleated cells. A polymerase chain reaction-based restriction fragment length polymorphism assay that used the restriction enzymes Rsa I and Dra I was used to detect wild-type and variant forms of the CYP2E1 gene. RESULTS: Individuals homozygous for an allele of the CYP2E1 gene that is detected by Rsa I digestion (c2 allele) were found to have an increased risk of nasopharyngeal carcinoma (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.2-5.7); this effect was limited to nonsmokers (RR = 9.3; 95% CI = 2.7-32) and was not affected by alcohol consumption. CONCLUSIONS: Our findings suggest that the CYP2E1 genotype is a determinant of nasopharyngeal carcinoma risk.

Determinants of polycyclic aromatic hydrocarbon-DNA adducts in human placenta.

To determine the relative contributions of tobacco smoking and P-450 metabolism (cytochrome P-450IAI) in the formation of benzo(a)pyrenediol-epoxide and other polycyclic aromatic hydrocarbon-DNA adducts in vivo, 16 human placentas were assayed for aryl hydrocarbon hydroxylase activity and (+/-)r-7,t-8-dihydroxy-c-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene-DN A adduct levels. Immunoaffinity chromatography columns, conjugated with monoclonal antibodies raised against benzo(a)-pyrene-diol-epoxide-deoxyguanosine, were used to concentrate polycyclic aromatic hydrocarbon-DNA adducted nucleotides, and synchronous fluorescence spectroscopy was used specifically to detect r-7,t-8,t-9,c-10-tetrahydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BP-tetrol) extracted from acid hydrolysates of immunoconcentrated materials. Data were analyzed for associations with maternal dietary and smoking habits, umbilical cord blood cotinine levels, and placental aryl hydrocarbon hydroxylase levels. Complex mixtures of fluorescent materials were present in organic solvent extracts of acid hydrolysates of immunoconcentrated nucleotide-adducts from all placentas with patterns of fluorescence that may be associated with tobacco smoking determined by generation of spectral fluorescence excitation-emission matrices. BP-tetrols were detected in extracts from 8 placentas: 5 of 7 from smokers and 3 of 9 from nonsmokers. Placental aryl hydrocarbon hydroxylase activity was significantly higher in placentas from which BP-tetrols were extracted [3.9 +/- 2.4 [corrected] (mean +/- SE) pmol 3-hydroxybenzo(a)pyrene mg protein-1 min-1], than among placentas from which BP-tetrols were not extracted (0.4 +/- 0.2 [corrected] pmol 3-hydroxybenzo(a)pyrene mg protein-1 min-1) (P = 0.03, Student's t test). This association was independent of maternal smoking or umbilical cord blood cotinine levels. These results indicate that while maternal tobacco smoking is associated with the accumulation of putative, but as yet unidentified, polycyclic aromatic hydrocarbon-DNA adducts in placenta, metabolic capacity appears to be the principal determinant for the (+/-)r-7,t-8-dihydroxy-c-9,10 epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene-DNA adduct levels detected.

Measurement of 4-aminobiphenyl-hemoglobin adducts in lung cancer cases and controls.

Hemoglobin adducts of the activated carcinogenic aromatic amine 4-aminobiphenyl have been measured in a case-control study of lung cancer. Data obtained for lung cancer cases are compared to those obtained for controls that consisted of patients with either chronic obstructive pulmonary disease or non-pulmonary cancers. Both simple and multivariate analysis found a positive association of 4-aminobiphenyl-hemoglobin adducts with the quantity of tobacco smoked as determined by either urine cotinine or questionnaire data. No association was found between 4-aminobiphenyl-hemoglobin adducts and cancer diagnosis, and adduct levels were not related to remote tobacco use, i.e., total pack years of smoking. There was no association between the levels of adducts detected and the ability of an individual to metabolize debrisoquine (debrisoquine metabolic phenotype, CYP2D6). Whereas 4-aminobiphenyl-hemoglobin adduct levels reflected recent tobacco smoking, they were not correlated with lung cancer risk.

Mutations of the K-ras and p53 genes in gastric adenocarcinomas from a high-incidence region around Florence, Italy.

K-ras and p53 gene mutations in intestinal-type gastric carcinomas from a high-incidence area around Florence, Italy, were studied by single strand conformation polymorphism and DNA sequencing analysis. Single-strand conformation polymorphism analysis of K-ras indicated aberrant bands in 13 of 34 cases. Sequencing revealed point mutations in 7 (including two at a previously unreported site in codon 11), a significantly higher frequency than reported in countries other than Japan. No K-ras mutations were identified in stage III tumors. Single-strand conformation polymorphisms in p53 exons 5-8 occurred in 30 of 34 cases, with mutations identifiable by direct sequencing in 65% of the cases. Of these, 91% were base substitutions, a value similar to that usually reported, but the percentage of G:C to A:T transitions (90% in this study, 89% in all published European cases combined) differed significantly from that in Oriental cases (48%). The percentage of A:T to G:C transitions was greater in Oriental (22%) than European cases (2%), as was also true for transversions (30% in Oriental tumors, 9% in European tumors). The frequency of mutations at CpG sites (14%) varied significantly from the 67% in cases from a neighboring region in Italy. Helicobacter pylori infection was established in 19 cases and was somewhat more common in cases lacking a p53 mutation.

Cytochrome P450IIE1 genetic polymorphisms, racial variation, and lung cancer risk.

Cytochrome P450IIE1 is responsible for the activation of carcinogenic N-nitrosamines, benzene, urethane, and other low-molecular-weight compounds. Restriction fragment length polymorphisms (PstI and RsaI restriction enzymes) have been identified in the cytochrome P450IIE1 transcription regulatory region that may affect expression. This study describes the PstI and RsaI polymorphisms in different racial populations and in a case-control study of lung cancer. The allelic frequencies were markedly different in Japanese, African-Americans, and Caucasians: the PstI rare allele was present at a frequency of 2% in Caucasians, 5% in African-Americans, and 24% in Japanese (P < 0.05). For the RsaI rare allele, frequencies were 2% in Caucasians, 2% in African-Americans, and 27% in Japanese (P < 0.05). The assay was also applied to 128 individuals enrolled in a case-control study of lung cancer. Although limited in statistical power, the data indicate no evidence for an association in the aggregate of cytochrome P450IIE1 PstI [for which the odds ratio was 0.7 (95% confidence interval (C.I.) = 0.2-2.8)] or RsaI [for which the odds ratio was 0.9 (95% C.I. = 0.2-5.4)] restriction fragment length polymorphisms with lung cancer in this U.S. population. When analyzed by race, the lung cancer odds ratio for the PstI mutant allele in African-Americans was 0.19 (95% C.I. = 0.03-1.38), and in Caucasians it was 4.13 (95% C.I. = 0.34-48.8). For the RsaI mutant allele, the odds ratios were 0.20 (95% C.I. = 0.02-2.43) and 4.28 (95% C.I. = 0.35-50.6), respectively. The ethnic differences of these restriction fragment length polymorphisms might be related to genetic susceptibilities for lung cancer among Caucasians and for gastric or esophageal cancer among Japanese.

Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans.

Heterocyclic aromatic amines (HAAs) are formed when meat juices are pyrolyzed. In humans HAAs are activated in vivo by cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2) to mutagens or carcinogens. While activity of NAT2 is noninducible, exposure to cigarettes, polycyclic aromatic hydrocarbons, and cruciferous vegetables has been shown to induce CYP1A2 activity in humans. To date, it is unknown if pan-fried meat, which is consumed at high levels in the United States, is capable of inducing CYP1A2. In order to address this issue, we measured CYP1A2 and NAT2 activities in 66 healthy nonsmokers (33 males and 33 females) in a controlled metabolic feeding study. The study was designed to minimize the influence of known inducers of CYP1A2. Subjects consumed meat pan-fried at a low temperature (100 degrees C) for 7 days followed by 7 days of meat pan-fried at a high temperature (250 degrees C). The low temperature-cooked meat had undetectable levels of HAAs while the high temperature-cooked meat contained high amounts of HAAs [9.0 ng/g of 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2.1 ng/g of 2-amino-3,7,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx), and 32.8 ng/g of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)]. In contrast, total polycyclic aromatic hydrocarbon content was similar in both meat samples (10.7 ng/g in low temperature-cooked meat and 10.1 ng/g in high temperature-cooked meat). At the end of each period, subjects were tested for CYP1A2 and NAT2 enzyme activity by caffeine metabolism phenotyping. NAT2 activity remained unchanged throughout the study while CYP1A2 activity increased in 47 of 65 (72%) of the subjects after consuming high temperature-cooked meat (P < 0.0002), suggesting induction by some compound(s) formed during high temperature cooking. If HAAs are shown to be human carcinogens in epidemiological studies, then meat cooked at high temperatures may pose an increased cancer risk because it contains both inducers of CYP1A2 and procarcinogens MeIQx, DiMeIQx, and PhIP known to be activated by this enzyme.

Association of rare alleles of the Harvey ras protooncogene locus with lung cancer.

The hypothesis that rare variable nucleotide tandem repeat alleles of the Ha-ras-1 polymorphism are an inherited predisposing factor in human lung carcinogenesis has been evaluated in an age, race, and smoking matched case-control study. Twenty-three different alleles were identified by their restriction fragment length in DNA isolated from peripheral blood lymphocytes and were categorized into three groups: common; intermediate; and rare. The frequencies of rare alleles in blacks with either squamous cell carcinoma, large cell carcinoma, or small cell carcinoma were found to be significantly higher than those among groups of control subjects that were comprised of chronic obstructive pulmonary disease patients and patients with cancer at sites other than the lung. A similar trend which did not reach statistical significance was observed in whites. These data are consistent with the hypothesis that inheritance of Ha-ras-1 rare restriction fragment length alleles represents a genetic risk factor for some human lung cancers. The biological basis of this observation remains to be clarified, and it is possible that ethnic variations in rare allele frequencies are responsible for the differences noted. However, the data suggest that further evaluation of the Ha-ras-1 polymorphism as a marker of individual lung cancer susceptibility is warranted.

Allelic deletion analysis of the FHIT gene predicts poor survival in non-small cell lung cancer.

The fragile histidine triad (FHIT) gene at chromosome 3p14.2 is a candidate tumor suppressor gene linked to cancers of the lung, breast, colon, pancreas, and head and neck. Reports of frequent allelic deletion and abnormal transcripts in primary lung tumors plus recent evidence that it is targeted by tobacco smoke carcinogens suggest that it plays an important role in lung carcinogenesis. Non-small cell lung carcinoma still maintains a poor 5-year survival rate with the stage of disease at presentation as a major determinant of prognosis. We examined for allelic deletion at the FHIT locus in a series of 106 non-small cell lung carcinomas for which a full clinical, epidemiological, and 5-year survival profile was available. We found an allelic deletion frequency of 38% at one or two intragenic microsatellites. Allelic deletion of FHIT was related to tumor histology with 4 of 20 adenocarcinomas (20%) displaying loss of heterozygosity (LOH) compared with 12 of 22 (55%) nonadenocarcinomas (P = 0.03). We found that 63% of tumors with LOH of FHIT also had p53 missense mutations whereas only 26% with LOH had wild type p53 negative sequence (P = 0.02). We also found a significant trend toward poorer survival in patients with LOH of at least one locus of the FHIT gene (log rank, P = 0.01). This survival correlation is independent of tumor stage, size, histological subtype, degree of differentiation, and p53 mutation status. Our data support the hypothesis that the loss of the FHIT contributes to the molecular pathogenesis of human lung cancer and is an indicator of poor prognosis.