The Effect of Polymorphisms in DNA Repair Genes and Carcinogen Metabolizers on Leukocyte Telomere Length: A Cohort of Healthy Spanish Smokers.

INTRODUCTION: Smoking implies exposure to carcinogenic agents that causes DNA damage, which could be suspected to enhance telomere attrition. To protect and deal with DNA damage, cells possess mechanisms that repair and neutralize harmful substances. Polymorphisms altering DNA repair capacity or carcinogen metabolism may lead to synergistic effects with tobacco carcinogen-induced shorter telomere length independently of cancer interaction. The aim of this study was to explore the association between leukocyte telomere length (LTL) and several genetic polymorphisms in DNA repair genes and carcinogen metabolizers in a cohort of healthy smokers. METHODS: We evaluated the effect of six genetic polymorphisms in cytochrome P1A1 (Ile462Val), XRCC1 (Arg399Gln), APEX1 (Asp148Glu), XRCC3 (Thr241Met), and XPD (Asp312Asn; Lys751Gln) on LTL in a cohort of 145 healthy smokers in addition to smoking habits. RESULTS: Logistic regression analysis showed an association between XRCC1 399Gln allele and shorter telomere length (OR = 5.03, 95% CI = 1.08% to 23.36%). There were not association between the rest of polymorphisms analyzed and LTL. CONCLUSIONS: Continuous exposure to tobacco could overwhelm the DNA repair machinery, making the effect of the polymorphisms that reduce repair capacity more pronounced. Analyzing the function of smoking-induced DNA-repair genes and LTL is an important goal in order to identify therapeutic targets to treat smoking-induced diseases.

Are SNP-Smoking Association Studies Needed in Controls? DNA Repair Gene Polymorphisms and Smoking Intensity.

Variations in tobacco-related cancers, incidence and prevalence reflect differences in tobacco consumption in addition to genetic factors. Besides, genes related to lung cancer risk could be related to smoking behavior. Polymorphisms altering DNA repair capacity may lead to synergistic effects with tobacco carcinogen-induced lung cancer risk. Common problems in genetic association studies, such as presence of gene-by-environment (G x E) correlation in the population, may reduce the validity of these designs. The main purpose of this study was to evaluate the independence assumption for selected SNPs and smoking behaviour in a cohort of 320 healthy Spanish smokers. We found an association between the wild type alleles of XRCC3 Thr241Met or KLC3 Lys751Gln and greater smoking intensity (OR = 12.98, 95% CI = 2.86-58.82 and OR=16.90, 95% CI=2.09-142.8; respectively). Although preliminary, the results of our study provide evidence that genetic variations in DNA-repair genes may influence both smoking habits and the development of lung cancer. Population-specific G x E studies should be carried out when genetic and environmental factors interact to cause the disease.

Effects of cigarette smoking and nicotine metabolite ratio on leukocyte telomere length.

Studies of the effects of smoking on leukocyte telomere length (LTL) using cigarettes smoked per day or pack years smoked (PYS) present limitations. Reported high levels of smoking may not increase toxin exposure levels proportionally. Nicotine metabolism ratio (NMR) predicts total cigarette puff volume and overall exposure based on total N-nitrosamines, is highly reproducible and independent of time since the last cigarette. We hypothesized that smokers with higher NMRs will exhibit increased total puff volume, reflecting efforts to extract more nicotine from their cigarettes and increasing toxin exposure. In addition, higher levels of smoking could cause a gross damage in LTL. The urinary cotinine, 3-OH cotinine and nicotine levels of 147 smokers were analyzed using a LC/MS system Triple-Q6410. LTL and CYP2A6 genotype was determined by PCR in blood samples. We found a significant association between NMR and CYP2A6 genotype. Reduction in LTL was seen in relation to accumulated tobacco consumption and years smoking when we adjusted for age and gender. However, there were no significant differences between NMR values and LTL. In our study the higher exposure was associated with lower number of PYS. Smokers with reduced cigarette consumption may exhibit compensatory smoking behavior that results in no reduced tobacco toxin exposure. Our results suggest that lifetime accumulated smoking exposure could cause a gross damage in LTL rather than NMR or PYS. Nevertheless, a combination of smoking topography (NMR) and consumption (PYS) measures may provide useful information about smoking effects on health outcomes.

Clinical utility and economic impact of conventional transbronchial needle aspiration of mediastinal lymphadenopathies in bronchogenic carcinoma.

OBJECTIVES: To analyze the clinical utility and economic impact of conventional transbronchial needle aspiration (TBNA) in patients with diagnosis of bronchogenic carcinoma (BC) and mediastinal lymphadenopathies in thoracic computed tomography (CT). To assess the predictive factors of valid aspirations. PATIENTS AND METHODS: Retrospective observational study between 2006 and 2011 of all TBNA performed in patients with final diagnosis of BC and accessible hilar or mediastinal lymphadenopathies on thoracic CT. RESULTS: We performed TBNA on 267 lymphadenopathies of 192 patients. In 34.9% of patients, two or more lymph nodes were biopsied. Valid aspirations were obtained in 153 patients (79.7%) that were diagnostic in 124 (64.6%). Multivariate analysis showed that factors associated with valid or diagnostic results are the diameter of the lymph node and the number of lymph nodes explored. TBNA was the only endoscopic technique that provided the diagnosis of BC in 54 patients (28.1%). Staging mediastinoscopy was avoided in 67.6% of patients. The prevalence of mediastinal lymph node involvement was 74.4%, sensitivity of TBNA was 86.2% and negative predictive value was 63.6%. Including mediastinoscopy and other avoided diagnostic techniques, TBNA saved 451.57 € per patient. CONCLUSIONS: TBNA is a clinically useful, cost-effective technique in patients with BC and mediastinal or hilar lymphadenopathies. It should therefore be performed on a regular basis during diagnostic bronchoscopy of these patients.

Vascular endothelial growth factor (VEGF) serum levels are associated with survival in early stages of lung cancer patients.

AIM: Evaluate the serum vascular endothelial growth factor (VEGF) levels in the prognosis of lung cancer patients. METHODS: Fifty-four serum samples were analyzed for VEGF concentrations (79.3% nonsmall cell lung cancer (NSCLC) and 20.7% small cell lung cancer). RESULTS: Patients with serum VEGF-A levels higher than the mean of the patients studied (434.93 pg/mL) presented a shorter median survival time than those with lower levels (p =.04), as in patients with NSCLC tumors (p =.04) and in those with stages I-II (p <.05), and high serum VEGF-A levels. CONCLUSION: Elevated VEGF serum levels have a negative prognostic impact on survival in NSCLC and early stages of lung cancer patients.

Prognostic significance of the expression of vascular endothelial growth factors A, B, C, and D and their receptors R1, R2, and R3 in patients with nonsmall cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer death in the world. The objective of this study was to investigate the expression of vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) in patients with nonsmall cell lung cancer (NSCLC) and its correlation with the prognosis for patients with lung cancer. METHODS: The expression status of VEGFs and VEGFRs was examined in 48 nonconsecutive specimens of primary lung cancer by immunohistochemistry. Correlations between the expression of VEGFs and VEGFRs and clinicopathologic parameters were analyzed. RESULTS: Nineteen of 48 samples (39.6%) were moderately/highly immunoreactive for VEGF-A, 6 samples (12.5%) were reactive for VEGF-B, 14 samples (29.2%) were reactive for VEGF-C, 11 samples (22.9%) were reactive for VEGF-D, 20 samples (41.7%) were reactive for VEGFR1, 26 samples (54.2%) were reactive for VEGFR2, 20 samples (41.7%) were reactive for VEGFR3, and 19 samples (39.6%) were reactive for nuclear expression of VEGFR3. Patients with moderate/high VEGF-C, VEGFR1, and VEGFR2 expression had worse survival, whereas patients with moderate/high VEGF-D and nuclear VEGFR3 expression had better survival. After adjusting according to tumor stage, VEGF-B and VEGF-D expression had a significant correlation with worse survival in patients with stage I and II disease. Patients with stage III and IV disease who had VEGFR1 and VEGFR2 expression had worse survival, whereas the expression of VEGF-D was correlated significantly with better survival. Finally, stage, VEGF-D expression, and VEGFR1 expression were significantly independent prognostic predictors. CONCLUSIONS: The results of the current study indicated that the over-expression of VEGFs and VEGFRs plays an important role in the survival of patients with NSCLC. The inclusion of angiogenic factors in the standard pathologic study of lung cancer may improve the clinical evaluation of patients with NSCLC.

[The EpicliCP-2003 study: A multicenter epidemiological and clinical study of lung cancer in Spain]. / Estudio multicéntrico epidemiológico-clínico de cáncer de pulmón en España (estudio EpicliCP-2003).

OBJECTIVE: Mortality due to lung cancer in Spain is increasing continuously. The aim of the present study was to collect information on the hospital incidence of lung cancer, as well as information on clinical management, in different regions of Spain. MATERIAL AND METHODS: A prospective observational study of patients diagnosed with lung cancer in 2003 was carried out in 13 centers in 9 autonomous communities. Epidemiological, clinical, diagnostic, and therapeutic variables were assessed. RESULTS: Of a total population of 2,726,601 inhabitants (1 346 483 men and 1 380 118 women), 1064 male and 125 female lung cancer patients were included. The incidence standardized to the world population varied between 42.4/100,000 and 61.8/100,000 in men and between 1.5/100,000 and 8.6/100,000 in women. Overall, 51% were aged over 70 years, and 97.5% of the men and 32% of the women were smokers or ex-smokers. Cytologic or histologic confirmation was obtained for 93.1% of the cases (20.8% of which were small cell lung cancers and 79.2% were non-small cell lung cancers). The main initial symptoms were cough, chest pain, and weight loss. In 13.7%, lung cancer was suspected because of abnormal chest x-ray. The percentage with clinical TNM stages I and II ranged from 6.3% to 26.9%. The most common stage was stage IV in all centers. The percentage of patients undergoing surgery ranged from 2.5% to 20.6%, with a mean of 14.8% (19.9% of whom were patients with non-small cell lung cancer); 27% received palliative treatment only. CONCLUSIONS: The proportion of women suffering from lung cancer increased with respect to previous studies, with notable differences among regions. Despite diagnostic improvements, the percentage of patients undergoing surgery is low, though interregional variation is considerable.