Association of blood mercury levels with nonmelanoma skin cancer in the U.S.A. using National Health and Nutrition Examination Survey data (2003-2016).

BACKGROUND: Some studies have reported increased incidence or mortality of lung and brain cancers associated with occupations involving potential mercury exposure. Epidemiological evidence related to skin cancer is also limited. OBJECTIVES: To investigate the association between blood mercury (Hg) levels and nonmelanoma skin cancer (NMSC). METHODS: We used National Health and Nutrition Examination Survey data from 2003 to 2016. The exposures were blood total (tHg), inorganic (iHg) and methylmercury (MeHg). The outcome was a self-reported diagnosis of NMSC. We included participants aged ≥ 20 years who had information on blood mercury and sociodemographic factors. We conducted a logistic regression analysis to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the risk of NMSC associated with quartiles of blood Hg, after adjusting for the sociodemographic factors and survey year. RESULTS: The number of participants was 29 413; mean age was 49 years and 52% were female. Compared with those with a tHg ≤ 0·47 µg L-1 (Q1), those with a tHg > 1·74 µg L-1 (Q4) had nearly double the odds of NMSC (OR 1·79, 95% CI 1·19-2·71; Ptrend = 0·004). Similarly, those in the highest quartile of MeHg (> 1·44 µg L-1 ) had 1·7 times greater odds of NMSC (OR 1·74, 95% CI 1·13-2·70; Ptrend = 0·01) than those in the lowest quartile (≤ 0·21 µg L-1 ). iHg levels were nonsignificantly positively associated with NMSC (Ptrend = 0·08). CONCLUSIONS: We found that higher blood tHg and MeHg levels were associated with a higher prevalence of NMSC. Linked Comment: Taylor. Br J Dermatol 2020; 183:413-414.

Kerosene lighting contributes to household air pollution in rural Uganda.

The literature on the contribution of kerosene lighting to indoor air particulate concentrations is sparse. In rural Uganda, kitchens are almost universally located outside the main home, and kerosene is often used for lighting. In this study, we obtained longitudinal measures of particulate matter 2.5 microns or smaller in size (PM2.5 ) from living rooms and kitchens of 88 households in rural Uganda. Linear mixed-effects models with a random intercept for household were used to test the hypotheses that primary reported lighting source and kitchen location (indoor vs outdoor) are associated with PM2.5 levels. During initial testing, households reported using the following sources of lighting: open-wick kerosene (19.3%), hurricane kerosene (45.5%), battery-powered (33.0%), and solar (1.1%) lamps. During follow-up testing, these proportions changed to 29.5%, 35.2%, 18.2%, and 9.1%, respectively. Average ambient, living room, and kitchen PM2.5 levels were 20.2, 35.2, and 270.0 µg/m3 . Living rooms using open-wick kerosene lamps had the highest PM2.5 levels (55.3 µg/m3 ) compared to those using solar lighting (19.4 µg/m3 ; open wick vs solar, P=.01); 27.6% of homes using open-wick kerosene lamps met World Health Organization indoor air quality standards compared to 75.0% in homes using solar lighting.

Cotton dust, endotoxin and cancer mortality among the Shanghai textile workers cohort: a 30-year analysis.

BACKGROUND: Although occupational exposure to cotton dust and endotoxin is associated with adverse respiratory health, associations with cancer are unclear. We investigated cancer mortality in relation to cotton dust and endotoxin exposure in the Shanghai textile workers cohort. METHODS: We followed 444 cotton textile and a reference group of 467 unexposed silk workers for 30 years (26 777 person-years). HRs for all cancers combined (with and without lung cancer) and gastrointestinal cancer were estimated in Cox regression models as functions of cotton textile work and categories of cumulative exposure (low, medium, high), after adjustment for covariates including pack-years smoked. Different lag years accounted for disease latency. RESULTS: Risks of mortality from gastrointestinal cancers and all cancers combined, with the exclusion of lung cancer, were increased in cotton workers relative to silk workers. When stratified by category of cumulative cotton exposure, in general, risks were greatest for 20-year lagged medium exposure (all cancers HR=2.7 (95% CI 1.4 to 5.2); cancer excluding lung cancer HR=3.4 (1.7-7.0); gastrointestinal cancer HR=4.1 (1.8-9.7)). With the exclusion of lung cancer, risks of cancer were more pronounced. When stratified by category of cumulative endotoxin exposure, consistent associations were not observed for all cancers combined. However, excluding lung cancer, medium endotoxin exposure was associated with all cancers and gastrointestinal cancer in almost all lag models. CONCLUSIONS: Cotton dust may be associated with cancer mortality, especially gastrointestinal cancer, and endotoxin may play a causative role. Findings also indirectly support a protective effect of endotoxin on lung cancer.

Genetic variants associated with severe pneumonia in A/H1N1 influenza infection.

The A/H1N1 influenza strain isolated in Mexico in 2009 caused severe pulmonary illness in a small number of exposed individuals. Our objective was to determine the influence of genetic factors on their susceptibility. We carried out a case-control association study genotyping 91 patients with confirmed severe pneumonia from A/H1N1 infection and 98 exposed but asymptomatic household contacts, using the HumanCVD BeadChip (Illumina, San Diego, CA, USA). Four risk single-nucleotide polymorphisms were significantly (p<0.0001) associated with severe pneumonia: rs1801274 (Fc fragment of immunoglobulin G, low-affinity IIA, receptor (FCGR2A) gene, chromosome 1; OR 2.68, 95% CI 1.69-4.25); rs9856661 (gene unknown, chromosome 3; OR 2.62, 95% CI 1.64-4.18); rs8070740 (RPA interacting protein (RPAIN) gene, chromosome 17; OR 2.67, 95% CI 1.63-4.39); and rs3786054 (complement component 1, q subcomponent binding protein (C1QBP) gene, chromosome 17; OR 3.13, 95% CI 1.89-5.17). All SNP associations remained significant after adjustment for sex and comorbidities. The SNPs on chromosome 17 were in linkage disequilibrium. These findings revealed that gene polymorphisms located in chromosomes 1 and 17 might influence susceptibility to development of severe pneumonia in A/H1N1 infection. Two of these SNPs are mapped within genes (FCGR2A, C1QBP) involved in the handling of immune complexes and complement activation, respectively, suggesting that these genes may confer risk due to increased activation of host immunity.

Body mass index is associated with the development of acute respiratory distress syndrome.

BACKGROUND: The relationship between body mass index (BMI) and development of acute respiratory distress syndrome (ARDS) is unknown. METHODS: A cohort study of critically ill patients at risk for ARDS was carried out. BMI was calculated from admission height and weight. Patients were screened daily for AECC (American European Consensus Committee)-defined ARDS and 60-day ARDS mortality. RESULTS: Of 1795 patients, 83 (5%) patients were underweight (BMI <18.5 kg/m(2)), 627 (35%) normal (BMI 18.5-24.9), 605 (34%) overweight (BMI 25-29.9), 364 (20%) obese (BMI 30-39.9) and 116 (6%) severely obese (BMI > or =40). Increasing weight was associated with younger age (p<0.001), diabetes (p<0.0001), higher blood glucose (p<0.0001), lower prevalence of direct pulmonary injury (p<0.0001) and later development of ARDS (p = 0.01). BMI was associated with ARDS on multivariate analysis (OR(adj) 1.24 per SD increase; 95% CI 1.11 to 1.39). Similarly, obesity was associated with ARDS compared with normal weight (OR(adj) 1.66; 95% CI 1.21 to 2.28 for obese; OR(adj) 1.78; 95% CI 1.12 to 2.92 for severely obese). Exploratory analysis in a subgroup of intubated patients without ARDS on admission (n = 1045) found that obese patients received higher peak (p<0.0001) and positive end-expiratory pressures (p<0.0001) than non-obese patients. Among patients with ARDS, increasing BMI was associated with increased length of stay (p = 0.007) but not with mortality (OR(adj) 0.89 per SD increase; 95% CI 0.71 to 1.12). CONCLUSION: BMI was associated with increased risk of ARDS in a weight-dependent manner and with increased length of stay, but not with mortality. Additional studies are needed to determine whether differences in initial ventilator settings may contribute to ARDS development in the obese.

Circulating adhesion molecules after short-term exposure to particulate matter among welders.

BACKGROUND: Studies from several countries indicate that welders experience increased risk of mortality and morbidity from ischaemic heart disease. Although the underlying mechanisms are unclear, vascular responses to particulate matter contained in welding fumes may play a role. To investigate this, we studied the acute effects of welding fume exposure on the endothelial component of vascular function, as measured by circulating adhesion molecules involved in leukocyte adhesion (sICAM-1 and sVCAM-1) and coagulation (vWF). METHODS: A panel of 26 male welders was studied repeatedly across a 6 h work-shift on a high exposure welding day and/or a low exposure non-welding day. Personal PM(2.5) exposure was measured throughout the work-shift. Blood samples were collected in the morning (baseline) prior to the exposure period, immediately after the exposure period, and the following morning. To account for the repeated measurements, we used linear mixed models to evaluate the effects of welding (binary) and PM(2.5) (continuous) exposure on each blood marker, adjusting for baseline blood marker concentration, smoking, age and time of day. RESULTS: Welding and PM(2.5) exposure were significantly associated with a decrease in sVCAM-1 in the afternoon and the following morning and an increase in vWF in the afternoon. CONCLUSIONS: The data suggest that welding and short-term occupational exposure to PM(2.5) may acutely affect the endothelial component of vascular function.

p53 Arg72Pro, MDM2 T309G and CCND1 G870A polymorphisms are not associated with susceptibility to esophageal adenocarcinoma.

p53 Arg72Pro, MDM2 T309G, and CCND1 G870A are functional single-nucleotide polymorphisms (SNPs) in key genes that regulate apoptosis and cell cycle. Variant genotypes of these SNPs have been associated with increased risk and earlier age of onset in some cancers. We investigated the association of these SNPs with susceptibility to esophageal adenocarcinoma in a large, North American case-control study. Three hundred and twelve cases and 454 cancer-free controls recruited in Boston, USA were genotyped for each of the three SNPs, and demographic and clinical data were collected. Genotype frequencies for each of the three SNPs did not deviate from the Hardy-Weinberg equilibrium, and did not differ between cases and controls. Odds ratios (OR), adjusted for clinical risk factors, for the homozygous variant genotypes were 0.99 (95% confidence interval [CI] 0.57-1.72) for p53 Pro/Pro, 0.81 (95% CI 0.52-1.28) for MDM2 G/G, and 0.97 (95% CI 0.64-1.49) for CCND1 A/A. The analysis was adequately powered (80%) to detect ORs of 1.37, 1.35, and 1.34 for each SNP, respectively. In contrast to the results of smaller published studies, no association between p53 Arg72Pro, MDM2 T309G, and CCND1 G870A SNPs and susceptibility to esophageal adenocarcinoma, age of onset, or stage of disease at diagnosis was detected.

Serum bilirubin levels on ICU admission are associated with ARDS development and mortality in sepsis.

BACKGROUND: Hyperbilirubinaemia is a common complication of sepsis. Elevated bilirubin may induce inflammation and apoptosis. It was hypothesised that increased serum bilirubin on Intensive Care Unit (ICU) admission contributes to sepsis-related acute respiratory distress syndrome (ARDS). METHODS: Serum bilirubin on ICU admission was measured in 1006 patients with sepsis. Serial serum bilirubin was analysed prospectively in patients with sepsis who had ARDS for a period of 28 days. The effects of clinical factors and variants of the UGT1A1 gene on serum bilirubin levels were determined. Outcomes were ARDS risk and mortality. RESULTS: During 60-day follow-up, 326 patients with sepsis developed ARDS, of whom 144 died from ARDS. The hyperbilirubinaemia (>or=2.0 mg/dl) rate in patients with ARDS (22.4%) was higher than in those without ARDS (14.1%, p = 0.002). For each 1.0 mg/dl increase in admission bilirubin, ARDS risk and 28- and 60-day ARDS mortalities were increased by 7% (OR = 1.07; p = 0.003), 20% (OR = 1.20; p = 0.002) and 18% (OR = 1.18; p = 0.004), respectively. Compared with subjects with bilirubin levels <2.0 mg/dl, patients with hyperbilirubinaemia had higher risks of ARDS (OR = 2.12; p = 0.0007) and 28-day (OR = 2.24; p = 0.020) and 60-day ARDS mortalities (OR = 2.09; p = 0.020). In sepsis-related ARDS, serial bilirubin levels in non-survivors were consistently higher than in survivors (p<0.0001). Clinical variables explained 29.5% of the interindividual variation in bilirubin levels, whereas genetic variants of UGT1A1 contributed 7.5%. CONCLUSION: In sepsis, a higher serum bilirubin level on ICU admission is associated with subsequent ARDS development and mortality.

Sex-specific association of epidermal growth factor gene polymorphisms with acute respiratory distress syndrome.

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance and inflammation, and is regulated by sex hormones. An unmatched, nested case-control study was conducted to evaluate the associations of EGF variants with acute respiratory distress syndrome (ARDS) and the role of sex on the associations between EGF variants and ARDS. Patients with ARDS risk factors upon intensive care unit admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1,052 Caucasians who did not develop ARDS. Cases were followed for clinical outcomes and 60-day mortality. One functional single nucleotide polymorphism (SNP), rs4444903, and six haplotype-tagging SNPs spanning the entire EGF gene were genotyped. No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Sex-stratified analyses showed opposite effects of EGF variants on ARDS in males versus in females. SNPs rs4444903, rs2298991, rs7692976 and rs4698803, and haplotypes GGCGTC and ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs6533485 significantly interacted with sex for ARDS risk. The present study suggests that associations of epidermal growth factor gene variants with acute respiratory distress syndrome risk are modified by sex. The current findings should be replicated in other populations.

Epidermal growth factor receptor polymorphisms and clinical outcomes in non-small-cell lung cancer patients treated with gefitinib.

The-216G/T, -191C/A, intron 1 and Arg497Lys epidermal growth factor receptor (EGFR) polymorphisms were evaluated in 92 advanced non-small-cell lung cancer patients treated with gefitinib, an EGFR tyrosine-kinase inhibitor. Improved progression free survival (PFS) was found in patients homozygous for the shorter lengths of intron 1 polymorphism (S/S; S=16 or fewer CA repeats; log-rank test (LRT) P=0.03) and for patients carrying any T allele of the -216G/T polymorphism (LRT, P=0.005). When considered together, patients with intron 1 S/S genotype and at least one T allele of -216G/T had improved PFS (LRT P=0.0006; adjusted hazard ratio (AHR), 0.60 (95% confidence interval, 0.36-0.98)) and overall survival (LRT P=0.02; AHR, 0.60 (0.36-1.00)) when compared with all others. The T allele of -216G/T was also associated with significantly higher rates of stable disease/partial response (P=0.01) and a significantly higher risk of treatment-related rash/diarrhea (P=0.004, multivariate model). EGFR intron 1 and -216G/T polymorphisms influence clinical outcomes in gefitinib-treated non-small-cell lung cancer patients.

Genetic susceptibility to occupational exposures.

Because of their high prevalence in the general population, genetic variants that determine susceptibility to environmental exposures may contribute greatly to the development of occupational diseases in the setting of specific exposures occurring in the workplace. Studies investigating genetic susceptibilities in the workplace may: (1) provide mechanistic insight into the aetiology of disease, in particular the determination of environmentally responsive genes; (2) identify susceptible subpopulations with respect to exposure; and (3) provide valuable input in setting occupational exposure limits by taking genetic susceptibility into account. Polymorphisms in the NAT2 and the HLA-DPB1(G)(lu69) genes provide classic examples of how genetic susceptibility markers have a clear role in identifying disease risk in bladder cancer and chronic beryllium disease, respectively. For diseases with more complex and multifactorial aetiology such as occupational asthma and chronic airways disease, susceptibility studies for selected genetic polymorphisms provide additional insight into the biological mechanisms of disease. Even when polymorphisms for genetic susceptibility have a clear role in identifying disease risk, the value of wide scale genetic screening in occupational settings remains limited due to primarily ethical and social concerns. Thus, large scale genetic screening in the workplace is not currently recommended.

Inhibition of T cell costimulation abrogates airway hyperresponsiveness in a murine model.

Activation of naive T cells requires at least two signals. In addition to the well characterized interaction of the T cell antigen receptor with the antigen/MHC expressed on an antigen-presenting cell, T cell activation also requires costimulation by a second set of signals. The best characterized costimulatory receptor is CD28, which binds to a family of B7 ligands expressed on antigen-presenting cells. In asthma, although activated T cells play a role in the initiation and maintenance of airway inflammation, the importance of T cell costimulation in bronchial hyperresponsiveness had not been characterized. Therefore, we tested the hypothesis that inhibition of the CD28:B7 costimulatory pathway would abrogate airway hyperresponsiveness. Our results show that blockade of costimulation with CTLA4-Ig, a fusion protein known to prevent costimulation by blocking CD28:B7 interactions, inhibits airway hyperresponsiveness, inflammatory infiltration, expansion of thoracic lymphocytes, and allergen-specific responsiveness of thoracic T cells in this murine model of allergic asthma.

Enhancement of benzo[a]pyrene-induced sister chromatid exchanges in lymphocytes from cigarette smokers occupationally exposed to asbestos.

The frequencies of base-line and benzo[a]pyrene [(BP) CAS 50-38-8]-induced sister chromatid exchanges (SCE) were measured in peripheral blood lymphocytes from 22 male asbestos-exposed workers and 10 nonexposed workers of comparable age. A clear association between cigarette smoking and asbestos exposure in the sensitivity of lymphocytes to BP was observed. Among asbestos-exposed workers, lymphocytes from those who smoked cigarettes were significantly more susceptible to the induction of SCE by in vitro exposure to BP (P = .01) than were lymphocytes from nonsmokers. Active smoking elevated the base-line SCE frequency in both asbestos-exposed and nonexposed workers (P = .001), and an interaction between smoking and asbestos in the production of base-line SCE was suggested (P = .07). Asbestos exposure alone was not associated with an enhanced susceptibility to the induction of SCE by BP or with an elevation of base-line SCE. Increased age was associated with an increase in SCE inducibility by BP (P = .01), and a history of smoking was marginally associated with SCE inducibility by BP (P = .07). These findings support the hypothesis that an increased susceptibility of asbestos-exposed individuals to polyaromatic hydrocarbon-induced cancer results from an enhanced sensitivity to the induction of genetic damage rather than to an asbestos-induced differential cellular metabolic capacity.

Early age at smoking initiation and tobacco carcinogen DNA damage in the lung.

BACKGROUND: DNA adducts formed as a consequence of exposure to tobacco smoke may be involved in carcinogenesis, and their presence may indicate a high risk of lung cancer. To determine whether DNA adducts can be used as a "dosimeter" for cancer risk, we measured the adduct levels in nontumorous lung tissue and blood mononuclear cells from patients with lung cancer, and we collected data from the patients on their history of smoking. METHODS: We used the 32P-postlabeling assay to measure aromatic hydrophobic DNA adducts in nontumorous lung tissue from 143 patients and in blood mononuclear cells from 54 of these patients. From the smoking histories, we identified exposure variables associated with increased DNA adduct levels by use of multivariate analyses with negative binomial regression models. RESULTS/ CONCLUSIONS: We found statistically significant interactions for variables of current and former smoking and for other smoking variables (e.g., pack-years [number of packs smoked per day x years of smoking] or years smoked), indicating that the impact of smoking variables on DNA adduct levels may be different in current and former smokers. Consequently, our analyses indicate that models for current and former smokers should be considered separately. In current smokers, recent smoking intensity (cigarettes smoked per day) was the most important variable. In former smokers, age at smoking initiation was inversely associated with DNA adduct levels. A highly statistically significant correlation (r=.77 [Spearman's correlation]; two sided P<.001) was observed between DNA adduct levels in blood mononuclear cells and lung tissue. IMPLICATIONS: Our results in former smokers suggest that smoking during adolescence may produce physiologic changes that lead to increased DNA adduct persistence or that young smokers may be markedly susceptible to DNA adduct formation and have higher adduct burdens after they quit smoking than those who started smoking later in life.

Implications and prognostic value of K-ras mutation for early-stage lung cancer in women.

BACKGROUND: Because there is no clear consensus as to the predictive value of K-ras gene mutation for survival in patients with lung cancer, we examined the occurrence of K-ras mutations in a large, prospective case series of non-small-cell lung cancer (NSCLC). Our goals were to define the patient characteristics associated with K-ras mutation and to determine whether mutation of this gene might be a biomarker of patient prognosis. METHODS: Consecutive, newly diagnosed patients with lung cancer treated with potentially curative resection over a 4-year period were recruited for study. The mutation status of K-ras codon 12 in each patient's tumor DNA was determined by means of polymerase chain reaction-restriction fragment length polymorphism analysis of archived pathology specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a statistically significant association between female sex and K-ras mutation after adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval [CI] = 1.3-7.9); mutations were found only in smokers. Comparison of Kaplan-Meier curves indicated a strong association between K-ras mutation and decreased patient survival (two-sided P =.009); analysis stratified by pathologic staging groups revealed that this association was statistically significant only for stage I tumors (two-sided P =.002). Cox proportional hazards modeling indicated that K-ras codon 12 mutation was a statistically significant predictor of patient survival, after adjustment for the effects of age, sex, and stage (risk ratio = 1.8; 95% CI = 1.1-3.1). CONCLUSIONS: After adjustment for environmental exposures, non-small-cell lung tumors in women appear to be more likely than those in men to harbor K-ras mutations, suggesting a possible role of estrogen exposure in either the initiation or the selection of K-ras mutant clones in adenocarcinoma. In addition, our data suggest that K-ras codon 12 mutation is a marker of aggressive NSCLC, as evidenced by its association with decreased patient survival, particularly for early-stage disease.

Chromosome 3p14 alterations in lung cancer: evidence that FHIT exon deletion is a target of tobacco carcinogens and asbestos.

Alterations in the FHIT gene region have been previously associated with smoking status and the occurrence of lung tumors. In the current study, we examined the nature of the mutations that occur at FHIT and the types of carcinogen exposures that are associated with FHIT alterations. We screened 40 primary lung tumors for the presence of point mutations within the coding exons of FHIT using PCR-single-strand conformational polymorphism. Tumors were also analyzed for allelic loss using microsatellite markers located in or near FHIT. No tumors contained point mutations within the coding region of the FHIT gene. However, several samples failed to generate a PCR product, suggesting that regions of the gene are homozygously deleted. Samples were reanalyzed for exon loss using PCR; 13 of 30 tumors failed to generate a PCR product, and 20 of 30 tumors were missing at least one FHIT exon or had loss (loss of heterozygosity or deletion) of one microsatellite marker, suggesting that regions of the gene are homozygously deleted. These data indicate that the FHIT gene has a novel pattern of mutational inactivation not seen previously with other tumor suppressor genes, most likely influenced by the proximity of the FRA3B region. There were no associations of age, sex, p53, or k-ras mutation and FHIT exon deletion. However, there was an association of smoking duration and asbestos exposure with FHIT exon loss, indicating that carcinogenic exposures may be causal in the generation of alterations in the FHIT region.

Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer.

The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer. The region at 3p21 is believed to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targeted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC). We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p21. LOH at 3p21 was analyzed for association with the clinical features of NSCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured using 32P-postlabeling) and carcinogen exposure information including cigarette smoking and asbestos exposure. Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH. None of the cancers showed BAT-26 instability. The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and was higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02). Our results confirm that 3p21 LOH is strongly associated with measures of biologically effective dose of exposure to tobacco carcinogens. Our results also suggest that alterations of hMLH1 are not related to any of the reported associations, because there was no evidence of microsatellite instability. Finally, LOH in 3p21 may be an early molecular event in NSCLC, because it is significantly associated with a tendency to start smoking at a young age.

Correlation of DNA adducts in blood mononuclear cells with tobacco carcinogen-induced damage in human lung.

The formation of carcinogen-DNA adducts within the respiratory epithelium is thought to be a critical factor in the induction of lung cancer from tobacco smoke. A reliable surrogate measure of carcinogen damage to the lung would be of great value in molecular epidemiological studies of cancer risk. The validity of measurements of DNA adducts formed from hydrophobic aromatic hydrocarbons in peripheral blood mononuclear cells (MNCs) was investigated by comparing the levels of aromatic DNA adducts detected in lung tissue from 31 lung cancer patients with those detected in MNCs from the same individuals using the 32P-postlabeling assay. The associations of smoking history and intake of dietary antioxidants with adduct levels also were assessed. Tissue-specific, as well as common DNA adducts were detected in lung and blood; total MNC adduct levels were highly correlated with total lung adducts. After smoking cessation, adduct levels appeared to decay in both tissues at similar rates. Multivariate analyses (Poisson regression modeling) indicated that dietary antioxidant intake (carotenoids, vitamin A, and retinol) modified the levels of aromatic DNA adducts in both the lungs and blood. Of all models tested, the optimal one for predicting lung adduct levels included the measure of blood MNC adduct levels only. Therefore, blood MNCs are a valid surrogate tissue for estimating the burden of DNA adducts in respiratory tissue in molecular epidemiological studies.

k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: asbestos-related cancer without asbestosis.

Environmental carcinogen exposure is requisite for the development of nearly all lung cancer, and it is well known that asbestos exposure interacts synergistically with tobacco smoke to induce lung cancer. However, the precise molecular lesions induced by asbestos are unknown. Furthermore, it is also unknown whether asbestos carcinogenesis proceeds in a fashion independent of or dependent upon the induction of fibrosis in workers with high asbestos exposures. Previous studies have suggested that asbestos is associated with the presence of a k-ras mutation in adenocarcinoma of the lung. We aimed to test whether occupational asbestos exposure was associated with k-ras codon 12 mutations in lung adenocarcinoma tumors and to determine whether this was conditional on the presence of asbestosis. All newly diagnosed, resectable lung cancer patients receiving treatment at the Massachusetts General Hospital between November 1992 and December 1996 were eligible to participate. Because k-ras mutation is very strongly associated with adenocarcinoma, and men were more likely to be occupationally exposed to asbestos, the study was restricted to males with this histological diagnosis. There were 84 male patients with available questionnaire-derived work history data and paraffin-embedded tumor tissue for determination of k-ras mutation status. Chest radiographic evaluation was done for all of the patients who reported occupational exposure to asbestos. The prevalence of k-ras mutation was higher among those with a history of occupational asbestos exposure (crude odds ratio, 4.8; 95% confidence interval, 1.5-15.4) compared to those without asbestos exposure, and this association remained after adjustment for age and pack-years smoked (adjusted odds ratio, 6.9; 95% confidence interval, 1.7-28.6). An index score that weights both the dates of exposure and the estimated intensity of exposure indicated that those with k-ras mutations had significantly greater asbestos exposures than those without mutations (P < 0.01). Analysis of the descriptive components of exposure indicated that the duration of exposure was not associated with k-ras mutation, but that the time since initial exposure was significantly associated with mutation status. The association of k-ras mutation and reported asbestos exposure was not dependent on the presence of radiographic evidence of asbestos-related disease. These data suggest that asbestos exposure increases the likelihood of mutation at k-ras codon 12 and that this process occurs independently of the induction of interstitial fibrosis.

p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer.

The p16(INK4a) protein inhibits cyclin-dependent kinase 4, a key regulator of progression through the G(1) phase of the cell cycle. Methylation of CpG islands in the promoter region is an important avenue for inactivation of p16. The mechanism of methylation of the p16 promoter region, however, has not been elucidated. Recent reports investigating p16 methylation in non-small cell lung cancer (NSCLC) suggest that carcinogens in tobacco smoke induce the DNA methylation process. We investigated the association between methylation of the p16 promoter region and exposure to tobacco smoke in 185 primary NSCLCS: We also studied the relationship of p16 methylation with mutation of the K-ras and p53 genes, as well as with methylation at the DAP-kinase and p14(ARF) loci. Finally, we evaluated the prognostic significance of p16 methylation in NSCLC. The prevalence of p16 methylation was greater in squamous cell carcinoma (41%) compared with adenocarcinoma (22%; P = 0.03; Fisher's exact test). Methylation of p16 was significantly associated with pack-years smoked (P = 0.007; Wilcoxon rank sum test), duration of smoking (P = 0.0009; Wilcoxon rank sum test), and negatively with the time since quitting smoking (P = 0.03; Wilcoxon rank sum test). No methylation of the nearby p14(ARF) locus was detected, and methylation of the DAP-kinase locus was not associated with either p16 methylation or with exposure to tobacco smoke. In patients with stage 1 adenocarcinoma, p16 methylation was an independent risk factor predicting significantly shorter postsurgery survival (P = 0.03), controlling for the significant effects of other factors, including K-ras mutation. These findings suggest that methylation of CpG islands in tobacco-associated cancers occurs in a gene- and tissue-specific manner and is induced directly or indirectly by exposure to tobacco smoke in NSCLC.