Adrian Cassidy

Publications of Adrian Cassidy

• Welding and Lung Cancer in Central and Eastern Europe and the United Kingdom.

  Authors: Andrea 't Mannetje, Paul Brennan, David Zaridze, Neonila Szeszenia-Dabrowska, Peter Rudnai, Jolanta Lissowska, Eleonóra Fabiánová, Adrian Cassidy, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Joelle Fevotte, Tony Fletcher, Paolo Boffetta

  American journal of epidemiology. 02/2012;

  Occupation as a welder has been associated with a 25%-40% increase in lung cancer risk. This study aims to elucidate to what extent confounding by smoking and asbestos drives this association and toOccupation as a welder has been associated with a 25%-40% increase in lung cancer risk. This study aims to elucidate to what extent confounding by smoking and asbestos drives this association and to evaluate the role of welding-related exposures such as chromium. The study included 2,197 male incident lung cancer cases and 2,295 controls from Romania, Hungary, Poland, Russia, Slovakia, the Czech Republic, and the United Kingdom from 1998 to 2001. Information on risk factors was collected through face-to-face interviews. Experts assessed exposure to 70 agents, and risk estimates were adjusted for smoking and occupational exposures. Occupation as a welder/flame cutter (prevalence controls: 3.7%) was associated with an odds ratio of 1.36 (95% confidence interval (CI): 1.00, 1.86) after adjustment for smoking and occupational exposures including asbestos. An odds ratio of 1.18 (95% CI: 1.01, 1.38) was found for welding fumes (prevalence controls: 22.8%), increasing to 1.38 for more than 25 exposure years (95% CI: 1.09, 1.75). A duration-response association was also observed for mild steel welding without chromium exposure. In this population, occupational exposure to welding fumes accounted for approximately 4% of lung cancer cases, to which both stainless and mild steel welding contributed equally. Given that welding remains a common task for many workers, exposure to welding fumes represents an important risk factor for lung cancer.

• Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies.

  Authors: Beate Pesch, Benjamin Kendzia, Per Gustavsson, Karl-Heinz Jöckel, Georg Johnen, Hermann Pohlabeln, Ann Olsson, Wolfgang Ahrens, Isabelle Mercedes Gross, Irene Brüske [......] Eleonora Fabianova, Rodica Stanescu Dumitru, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Charles M Rudin, Paul Brennan, Paolo Boffetta, Kurt Straif, Thomas Brüning

  International journal of cancer. Journal international du cancer. 11/2011;

  Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasetsLung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. By using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% confidence interval (CI): 74.8-143.2) for SqCC, 111.3 (95% CI: 69.8-177.5) for SCLC and 21.9 (95% CI: 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI: 31.5-124.6), 108.6 (95% CI: 50.7-232.8) and 16.8 (95% CI: 9.2-30.6), respectively. Although ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.

• Occupational exposure to metal compounds and lung cancer. Results from a multi-center case-control study in Central/Eastern Europe and UK.

  Authors: Andrea 't Mannetje, Vladimir Bencko, Paul Brennan, David Zaridze, Neonila Szeszenia-Dabrowska, Peter Rudnai, Jolanta Lissowska, Eleonóra Fabiánová, Adrian Cassidy, Dana Mates, Lenka Foretova, Vladimir Janout, Joelle Fevotte, Tony Fletcher, Paolo Boffetta

  Cancer causes & control : CCC. 09/2011; 22(12):1669-80.

  To study the association between occupational exposure to metals including chromium, cadmium, nickel, and arsenic compounds, within a population-based study design, while adjusting for confoundingTo study the association between occupational exposure to metals including chromium, cadmium, nickel, and arsenic compounds, within a population-based study design, while adjusting for confounding factors. A population-based lung cancer case-control study in Central/Eastern Europe and UK was conducted in 1998-2003, including 2,853 cases and 3,104 controls. Exposure to 70 occupational agents was assessed by local expert-teams for all subjects. Odds ratios (OR) for exposure to dust and fumes/mist of chromium, nickel, cadmium, arsenic, as well as inorganic pigment dust and inorganic acid mist, were adjusting for smoking, age, center, sex, and exposure to other occupational agents including the metals under study. Exposure to arsenic (prevalence = 1.4%) was associated with an increased lung cancer risk ((OR) 1.65, 95% confidence interval (95% CI):1.05-2.58). For chromium dust (prevalence = 4.8%, OR: 1.25, 95% CI: 0.95-1.65), a linear upward trend for duration and cumulative exposure was observed. A weak association was observed for exposure to cadmium fumes (prevalence = 1.8%, OR: 1.19, 95% CI: 0.77-1.82), which was strongest for the highest category of cumulative exposure (OR: 2.04, 95% CI: 1.07-3.90). No increased risk was observed for inorganic acid mist, inorganic pigment dust, or nickel, after adjustment for other metals. An independent effect of nickel cannot be excluded, due to its collinearity with chromium exposure. Occupational exposure to metals is an important risk factor for lung cancer. Although the strongest risk was observed for arsenic, exposure to chromium dust was most important in terms of attributable risk due to its high prevalence.

• Occupational exposure to organic dust increases lung cancer risk in the general population.

  Authors: Susan Peters, Hans Kromhout, Ann C Olsson, Heinz-Erich Wichmann, Irene Brüske, Dario Consonni, Maria Teresa Landi, Neil Caporaso, Jack Siemiatycki, Lorenzo Richiardi [......] Vladimir Janout, Isabelle Stücker, Rodica Stanescu Dumitru, Simone Benhamou, Bas Bueno-de-Mesquita, Benjamin Kendzia, Beate Pesch, Kurt Straif, Thomas Brüning, Roel Vermeulen

  Thorax. 08/2011; 67(2):111-6.

  Organic dust is a complex mixture of particulate matter from microbial, plant or animal origin. Occupations with exposure to animal products have been associated with an increased lung cancer risk,Organic dust is a complex mixture of particulate matter from microbial, plant or animal origin. Occupations with exposure to animal products have been associated with an increased lung cancer risk, while exposure to microbial components (eg, endotoxin) has been associated with a decreased risk. To date there has not been a comprehensive evaluation of the possible association between occupational organic dust exposure (and its specific constituents) and lung cancer risk in the general population. The SYNERGY project has pooled information on lifetime working and smoking from 13 300 lung cancer cases and 16 273 controls from 11 case-control studies conducted in Europe and Canada. A newly developed general population job-exposure matrix (assigning no, low or high exposure to organic dust, endotoxin, and contact with animals or fresh animal products) was applied to determine level of exposure. ORs for lung cancer were estimated by logistic regression, adjusted for age, sex, study, cigarette pack-years, time since quitting smoking, and ever employment in occupations with established lung cancer risk. Occupational organic dust exposure was associated with increased lung cancer risk. The second to the fourth quartile of cumulative exposure showed significant risk estimates ranging from 1.12 to 1.24 in a dose-dependent manner (p<0.001). This association remained in the highest quartile after restricting analyses to subjects without chronic obstructive pulmonary disease or asthma. No association was observed between lung cancer and exposure to endotoxin or contact with animals or animal products. Occupational exposure to organic dust was associated with increased lung cancer risk in this large pooled case-control study.

• Genome-wide association study of survival in non-small cell lung cancer patients receiving platinum-based chemotherapy.

  Authors: Xifeng Wu, Yuanqing Ye, Rafael Rosell, Christopher I Amos, David J Stewart, Michelle A T Hildebrandt, Jack A Roth, John D Minna, Jian Gu, Jie Lin [......] Jose Luis Ramirez Serrano, Miquel Taron, Adrian Cassidy, Charles Lu, Joe Y Chang, Scott M Lippman, Waun Ki Hong, Margaret R Spitz, Marjorie Romkes, Ping Yang

  Journal of the National Cancer Institute. 05/2011; 103(10):817-25.

  Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC). To identifyInterindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non-small cell lung cancer (NSCLC). To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307,260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided. SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10(-6)), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10(-7)). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10(-6)) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35). These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.

• Comparison of exposure assessment methods for occupational carcinogens in a multi-centre lung cancer case-control study.

  Authors: Susan Peters, Roel Vermeulen, Adrian Cassidy, Andrea 't Mannetje, Martie van Tongeren, Paolo Boffetta, Kurt Straif, Hans Kromhout

  Occupational and environmental medicine. 02/2011; 68(2):148-53.

  Retrospective exposure assessment remains a problematic aspect of population-based case-control studies. Different methods have been developed, including case-by-case expert assessment andRetrospective exposure assessment remains a problematic aspect of population-based case-control studies. Different methods have been developed, including case-by-case expert assessment and job-exposure matrices (JEM). The present analyses compare exposure prevalence and risk estimates derived by different exposure assessment methods. In the context of a case-control study conducted in seven European countries, exposure was estimated for asbestos, diesel motor emissions (DME) and crystalline silica, using three different assessment methods. First, experts assigned exposures to all reported jobs on a case-by-case basis. Second, a population-specific JEM (PSJEM) was developed using the expert assessments of controls only, and re-applied to all study subjects. Third, an independent general population JEM (GPJEM) was created by occupational exposure experts not involved in the original study, and applied to study subjects. Results from these methods were compared. There was poor to fair agreement in assigned exposure between expert assessment and the GPJEM (kappas: asbestos 0.17; DME 0.48; silica 0.38). Exposure prevalence was significantly heterogeneous (p<0.01) between countries for all three agents and assessment methods. For asbestos and DME, significant country heterogeneity in risk estimates was observed when using expert assessment. When applying the GPJEM, the heterogeneity in risk estimates for asbestos and, to some extent, silica diminished. It has been previously advocated that the expert assessment approach to assign exposures based on detailed questionnaire responses provides more accurate exposure estimates than JEM-based results. However, current results demonstrated little, if any, advantage of case-by-case assessment when compared to a JEM approach.

• Exposure to diesel motor exhaust and lung cancer risk in a pooled analysis from case-control studies in Europe and Canada.

  Authors: Ann C Olsson, Per Gustavsson, Hans Kromhout, Susan Peters, Roel Vermeulen, Irene Brüske, Beate Pesch, Jack Siemiatycki, Javier Pintos, Thomas Brüning [......] Peter Rudnai, Eleonora Fabianova, Rodica Stanescu Dumitru, Isabelle M Gross, Benjamin Kendzia, Francesco Forastiere, Bas Bueno-de-Mesquita, Paul Brennan, Paolo Boffetta, Kurt Straif

  American journal of respiratory and critical care medicine. 10/2010; 183(7):941-8.

  Diesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lackDiesel motor exhaust is classified by the International Agency for Research on Cancer as probably carcinogenic to humans. The epidemiologic evidence is evaluated as limited because most studies lack adequate control for potential confounders and only a few studies have reported on exposure-response relationships. Investigate lung cancer risk associated with occupational exposure to diesel motor exhaust, while controlling for potential confounders. The SYNERGY project pooled information on lifetime work histories and tobacco smoking from 13,304 cases and 16,282 controls from 11 case-control studies conducted in Europe and Canada. A general population job exposure matrix based on ISCO-68 occupational codes, assigning no, low, or high exposure to diesel motor exhaust, was applied to determine level of exposure. Odds ratios of lung cancer and 95% confidence intervals were estimated by unconditional logistic regression, adjusted for age, sex, study, ever-employment in an occupation with established lung cancer risk, cigarette pack-years, and time-since-quitting smoking. Cumulative diesel exposure was associated with an increased lung cancer risk highest quartile versus unexposed (odds ratio 1.31; 95% confidence interval, 1.19-1.43), and a significant exposure-response relationship (P value < 0.01). Corresponding effect estimates were similar in workers never employed in occupations with established lung cancer risk, and in women and never-smokers, although not statistically significant. Our results show a consistent association between occupational exposure to diesel motor exhaust and increased risk of lung cancer. This association is unlikely explained by bias or confounding, which we addressed by adjusted models and subgroup analyses.

• Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project.

  Authors: Olaide Y Raji, Olorunsola F Agbaje, Stephen W Duffy, Adrian Cassidy, John K Field

  Cancer prevention research (Philadelphia, Pa.). 05/2010; 3(5):664-9.

  The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphicThe Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into "low-risk" or "high-risk" group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk.

• A systematic review of occupational exposure to particulate matter and cardiovascular disease.

  Authors: Shona C Fang, Adrian Cassidy, David C Christiani

  International journal of environmental research and public health. 04/2010; 7(4):1773-806.

  Exposure to ambient particulate air pollution is a recognized risk factor for cardiovascular disease; however the link between occupational particulate exposures and adverse cardiovascular events isExposure to ambient particulate air pollution is a recognized risk factor for cardiovascular disease; however the link between occupational particulate exposures and adverse cardiovascular events is less clear. We conducted a systematic review, including meta-analysis where appropriate, of the epidemiologic association between occupational exposure to particulate matter and cardiovascular disease. Out of 697 articles meeting our initial criteria, 37 articles published from January 1990 to April 2009 (12 mortality; 5 morbidity; and 20 intermediate cardiovascular endpoints) were included. Results suggest a possible association between occupational particulate exposures and ischemic heart disease (IHD) mortality as well as non-fatal myocardial infarction (MI), and stronger evidence of associations with heart rate variability and systemic inflammation, potential intermediates between occupational PM exposure and IHD. In meta-analysis of mortality studies, a significant increase in IHD was observed (meta-IRR = 1.16; 95% CI: 1.06-1.26), however these data were limited by lack of adequate control for smoking and other potential confounders. Further research is needed to better clarify the magnitude of the potential risk of the development and aggravation of IHD associated with short and long-term occupational particulate exposures and to clarify the clinical significance of acute and chronic changes in intermediate cardiovascular outcomes.

• Family history and lung cancer risk: international multicentre case-control study in Eastern and Central Europe and meta-analyses.

  Authors: Jolanta Lissowska, Lenka Foretova, Joanna Dabek, David Zaridze, Neonila Szeszenia-Dabrowska, Peter Rudnai, Eleonora Fabianova, Adrian Cassidy, Dana Mates, Vladimir Bencko, Vladimir Janout, Rayjean J Hung, Paul Brennan, Paolo Boffetta

  Cancer causes & control : CCC. 03/2010; 21(7):1091-104.

  Lung cancer is the most common neoplastic disease in Eastern and Central Europe. The role of hereditary factors in lung carcinogenesis is not fully understood. Family history (FH) of lung cancer andLung cancer is the most common neoplastic disease in Eastern and Central Europe. The role of hereditary factors in lung carcinogenesis is not fully understood. Family history (FH) of lung cancer and other tobacco-related cancers might be a strong predictor of the lung cancer risk. We investigated family history of cancer among first-degree relatives of 2,861 patients with lung cancer and 3,118 controls from the Czech Republic, Hungary, Poland, Romania, Russia, Slovakia, and United Kingdom within the IARC Multicenter Case-Control Study. Odds ratios (ORs) and 95% CI were calculated using logistic regression, adjusting for age, gender, study center, education, tobacco smoking, and number of first-degree relatives. In addition, we conducted a meta-analysis of 41 studies on FH of cancer and lung cancer risk. Positive FH of lung cancer increased risk of lung cancer with OR of 1.63 (95%CI: 1.31-2.01), and having two or more affected relatives with lung cancer further increased the risk of lung cancer with OR 3.60 (95%CI: 1.56-8.31). Among subjects aged less than 50, the OR for FH of lung cancer was 2.08 (95%CI: 1.18-3.63). The associations were generally stronger for squamous cell carcinoma and large cell carcinoma subtypes. Heterogeneity in results was not found with respect to smoking status and gender. A significant association was not observed for FH of other smoking-related tumors. The results of meta-analysis were consistent with that of our study with regard to young onset, non-smokers and histology. FH of lung cancer is a predictor of an increased risk of lung cancer, especially in subjects aged less than 50.

• Risk of urinary bladder cancer: a case-control analysis of industry and occupation.

  Authors: Adrian Cassidy, Wei Wang, Xifeng Wu, Jie Lin

  BMC cancer. 12/2009; 9(1):443.

  ABSTRACT: BACKGROUND: Uncertainty remains about urinary bladder cancer (UBC) risk for many occupations. Here, we investigate the association between occupation, industry and UBC. METHODS: LifetimeABSTRACT: BACKGROUND: Uncertainty remains about urinary bladder cancer (UBC) risk for many occupations. Here, we investigate the association between occupation, industry and UBC. METHODS: Lifetime occupational history was collected by in-person interview for 604 newly diagnosed UBC patients and 604 cancer-free controls. Each job title was assigned a two-digit industry code and a three-digit occupation code. Odds ratios (ORs) for UBC associated with ever being employed in an industry or occupation were calculated by unconditional logistic regression adjusting for age, gender and smoking status. We also examined UBC risk by duration of employment (>0 to <10, greater than or equal to 10 years) in industry or occupation. RESULTS: Significantly increased risk of UBC was observed among waiters and bartenders (OR 2.87; 95% CI 1.05 to 7.72) and occupations related to medicine and health (OR 2.17; 95% CI 1.21 to 3.92), agricultural production, livestock and animal specialties (OR 1.90; 95% CI 1.03 to 3.49), electrical assembly, installation and repair (OR 1.69; 95% CI 1.07 to 2.65), communications (OR 1.74; 95% CI 1.00 to 3.01), and health services (OR 1.58; 95% CI 1.02 to 2.44). For these occupations we also observed a significant excess risk of UBC for long-term work (i.e. [greater than or equal to]10 years), with the exception of waiters and bartenders. Employment for 10 years or more was associated with increased risk of UBC in general farmers (OR 9.58; 95% CI 2.18 to 42.05), agricultural production of crops (OR 3.36; 95% CI 1.10 to 10.27), occupations related to bench working (OR 4.76; 95% CI 1.74 to 13.01), agricultural, fishery, forestry & related (OR 4.58; 95% CI 1.97 to 10.65), transportation equipment (OR 2.68; 95% CI 1.03 to 6.97), and structural work (OR 1.85; 95% CI 1.16 to 2.95). CONCLUSIONS: This study provides evidence of increased risk of UBC for occupations that were previously reported as at-risk. Workers in several occupation and industry groups have a significantly higher risk of UBC, particularly when duration of employment is 10 years or more.

• Genetic variations in PI3K-AKT-mTOR pathway and bladder cancer risk.

  Authors: Meng Chen, Adrian Cassidy, Jian Gu, George L Delclos, Fan Zhen, Hushan Yang, Michelle Hildebrandt, Jie Lin, Yuanqing Ye, Robert M Chamberlain, Colin P Dinney, Xifeng Wu

  Carcinogenesis. 10/2009;

  Genetic variations in PI3K-AKT-mTOR pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single nucleotide polymorphisms (SNPs) inGenetic variations in PI3K-AKT-mTOR pathway may affect critical cellular functions and increase an individual's cancer risk. We systematically evaluate 231 single nucleotide polymorphisms (SNPs) in 19 genes in the PI3K-AKT-mTOR signaling pathway as predictors of bladder cancer risk. In individual SNP analysis, 4 SNPs in RAPTOR remained significant after correcting for multiple testing: rs11653499 (OR: 1.79, 95%CI: 1.24-2.60, P = 0.002), rs7211818 (OR: 2.13, 95%CI: 1.35-3.36, P = 0.001), rs7212142 (OR: 1.57, 95%CI: 1.19-2.07, P = 0.002), and rs9674559 (OR: 2.05, 95%CI: 1.31-3.21, P = 0.002), among which rs7211818 and rs9674559 are within the same haplotype block. In haplotype analysis, compared to the most common haplotypes, haplotype containing the rs7212142 wild type allele showed a protective effect of bladder cancer (OR:0.83, 95%CI: 0.70-0.97). In contrast, the haplotype containing the rs7211818 variant allele showed a 1.32-fold elevated bladder cancer risk (95%CI: 1.09-1.60). In combined analysis of 3 independent significant RAPTOR SNPs (rs11653499, rs7211818, and rs7212142), a significant trend was observed for increased risk with an increase in the number of unfavorable genotypes (P for trend<0.001). Compared to the subjects without any of the unfavorable genotypes, those carrying all 3 unfavorable genotypes showed a 2.22 fold (95%CI: 1.33-3.71) fold increased bladder cancer risk. This is the first study to evaluate the role of germline genetic variations in PI3K-AKT-mTOR pathway as cancer susceptibility factors which will help us identify high risk individuals for bladder cancer.

• Use of lung cancer risk models in planning research and service programs in CT screening for lung cancer.

  Authors: Stephen W Duffy, Olaide Y Raji, Olorunsola F Agbaje, Prue C Allgood, Adrian Cassidy, John K Field

  Expert review of anticancer therapy. 10/2009; 9(10):1467-72.

  Computed tomography screening for lung cancer is now being tested in a number of international trials. The long-term success of the approach in the future National Screening Programme is dependentComputed tomography screening for lung cancer is now being tested in a number of international trials. The long-term success of the approach in the future National Screening Programme is dependent upon identifying populations at sufficient risk of lung cancer that the benefit-harm ratio of the intervention is likely to be high. There are a number of lung cancer risk prediction models currently available. We review these, and demonstrate, using the Liverpool Lung Project risk prediction model as a case study, the potential for use of a risk prediction model in the design of a randomized trial of lung cancer screening and in the planning of a service screening program.

• Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: a Multicenter Study in Europe.

  Authors: Ann C Olsson, Joelle Fevotte, Tony Fletcher, Adrian Cassidy, Andrea 't Mannetje, David Zaridze, Neonila Szeszenia-Dabrowska, Peter Rudnai, Jolanta Lissowska, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Paul Brennan, Paolo Boffetta

  Occupational and environmental medicine. 09/2009;

  BACKGROUND: Lung cancer incidence in Central and Eastern Europe (CEE) is among the highest in the world, and the role of occupational exposures has not been adequately studied in these countries.BACKGROUND: Lung cancer incidence in Central and Eastern Europe (CEE) is among the highest in the world, and the role of occupational exposures has not been adequately studied in these countries. OBJECTIVES: To investigate the contribution of occupational exposure to polycyclic aromatic hydrocarbons (PAH) to lung cancer in CEE. METHODS: A case-control study was conducted in Czech Republic, Hungary, Poland, Romania, Russia, and Slovakia, as well as the United Kingdom (UK) between 1998 and 2002. Occupational and socio-demographic information was collected through interviews from 2861 newly diagnosed lung cancer cases and 2936 population or hospital controls. Industrial hygiene experts in each country evaluated exposure to 70 occupational agents, whereof 15 mixtures containing PAH. Odds ratios (OR) of lung cancer were calculated after adjusting for other occupational exposures and tobacco smoking. RESULTS: The OR for ever-exposure to PAH in the CEE countries was 0.93 (95% CI 0.77-1.14). The OR for the highest category of cumulative exposure, duration of exposure and intensity of exposure were 1.13 (95% CI 0.80-1.58), 1.02 (95% CI 0.66-1.57) and 1.11 (95% CI 0.60-2.05), respectively. The OR for ever PAH exposure in the UK was 1.97 (95% CI 1.16-3.35). CONCLUSION: Occupational PAH exposure does not appear to substantially contribute to the burden of lung cancer in CEE. The apparently stronger effect observed in the UK may be due to high exposure levels and a joint effect with asbestos.

• Socioeconomic indicators and risk of lung cancer in Central and Eastern Europe.

  Authors: Frantiska Hrubá, Eleonóra Fabiáová, Vladimír Bencko, Adrian Cassidy, Jolanta Lissowska, Dana Mates, Péter Rudnai, David Zaridze, Lenka Foretová, Vladimir Janout, Neonilia Szeszenia-Dabrowska, Paul Brennan, Paolo Boffetta

  Central European journal of public health. 09/2009; 17(3):115-21.

  BACKGROUND: Social inequalities have been shown to contribute to the risk of lung cancer in industrialized countries, but it is unclear whether they also play a role in former socialist countries ofBACKGROUND: Social inequalities have been shown to contribute to the risk of lung cancer in industrialized countries, but it is unclear whether they also play a role in former socialist countries of Europe. METHODS: A case-control study involving 3,403 cases and 3,670 controls was conducted in Central European countries (Czech Republic, Hungary, Poland, Romania, Slovakia), Russia, and in the UK. Indicators of socioeconomic status, including education and white/blue collar occupation based on lifetime occupations were analysed as indicators of risk factors for lung cancer development, after adjustment for tobacco smoking and exposure to occupational carcinogens. RESULTS: Both indicators of socioeconomic status: low education and blue collar occupations were found as significant risk factors for lung cancer in men. The odds ratio of lung cancer for blue collar occupations compared to white collar occupations was 1.37 (95% confidence interval 1.15-1.62), that for low education compared to high education (analysis restricted to Central European countries) was 1.35 (95% confidence interval 1.03-1.77). No such effects were observed in women. CONCLUSIONS: The confirmation of the significant inverse association between the indicators of socioeconomic status and lung cancer risk in men may serve as a strong incentive for adoption of occupational and public health measures in lung cancer prevention.

• Cancer diagnosis in first-degree relatives and non-small cell lung cancer risk: Results from a multi-centre case-control study in Europe.

  Authors: Adrian Cassidy, Jessica Balsan, Aurélien Vesin, Xifeng Wu, Triantafillos Liloglou, Christian Brambilla, Jean-François Timsit, John K Field

  European journal of cancer (Oxford, England : 1990). 06/2009;

  Because aggregation of cancers at different sites can occur in families, cancer could be considered as a broad phenotype with shared genetic factors. Here, we report results from a multi-centreBecause aggregation of cancers at different sites can occur in families, cancer could be considered as a broad phenotype with shared genetic factors. Here, we report results from a multi-centre case-control study of non-small cell lung cancer (NSCLC), with particular emphasis on a history of cancer in first-degree relatives and the risk of lung cancer. From 2002 to 2006, 733 NSCLC patients treated surgically were recruited in 8 European countries and matched to 1312 controls, by centre, sex and age. We used multivariate conditional logistic regression models to test the association between a history of cancer in first-degree relatives and risk of NSCLC. A family history of lung cancer was associated with an odds ratio (OR) for early-onset (54years or younger) NSCLC of 4.72 (95% confidence interval [CI]=1.02-21.90). A family history of gastric cancer was associated with an OR for NSCLC of 1.82 (95% CI=1.08-3.06) and for late-onset (55years or older) NSCLC of 2.92 (95% CI=1.10-7.75). Our findings provide further evidence of a familial predisposition to lung cancer and support the hypothesis that family history is a significant risk factor for the disease. Because of the inherent potential for bias in familial case-control study design, cautious interpretation is warranted.

• Family History and Risk of Renal Cell Carcinoma: Results from a Case-Control Study and Systematic Meta-Analysis.

  Authors: Jessica Clague, Jie Lin, Adrian Cassidy, Surena Matin, Nizar M Tannir, Pheroze Tamboli, Christopher G Wood, Xifeng Wu

  Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 03/2009;

  We conducted a case-control analysis, a family-based population analysis, and a meta-analysis to assess the role of family history of cancer and kidney cancer in association with the risk of renalWe conducted a case-control analysis, a family-based population analysis, and a meta-analysis to assess the role of family history of cancer and kidney cancer in association with the risk of renal cell carcinoma (RCC). A total of 325 cases and 329 controls were identified from an ongoing case-control study of RCC. Study variables were assessed through 45-minute structured face-to-face interviews. In the case-control analysis, a family history of any cancer (in first-degree relatives) was associated with a nonsignificant 1.2-fold increase in RCC risk [95% confidence interval (95% CI), 0.8-1.6]. The risk increased to 1.7 and became significant when the relative was a sibling (95% CI, 1.1-2.5). A family history of kidney cancer (kidney cancer in first-degree relatives) was associated with a 4.3-fold significantly increased risk of RCC (95% CI, 1.6-11.9). The cases reported a total of 2,536 first-degree relatives of which 21 (0.8%) had kidney cancer, and the controls reported a total of 2,333 first-degree relatives of which 5 (0.2%) had kidney cancer (P = 0.003). In the family-based population analysis, a family history of kidney cancer was associated with a 2.8-fold increased risk of RCC (95% CI, 1.0-7.8). The meta-analysis further confirmed this significant association with a 2.2-fold increased risk of RCC (95% CI, 1.6-2.9). To our knowledge, this is the first study to use three analytic strategies to investigate the association between a family history of kidney cancer and risk of RCC, and the first systematic evaluation of the relative risk for developing RCC associated with family history.(Cancer Epidemiol Biomarkers Prev 2008;18(3):801-7).

• Lung cancer susceptibility locus at 5p15.33.

  Authors: James D McKay, Rayjean J Hung, Valerie Gaborieau, Paolo Boffetta, Amelie Chabrier, Graham Byrnes, David Zaridze, Anush Mukeria, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska [......] Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Fumihiko Matsuda, Helene Blanche, Ivo Gut, Simon Heath, Mark Lathrop, Paul Brennan

  Nature genetics. 01/2009; 40(12):1404-6.

  We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33,We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 x 10(-7) and P = 4 x 10(-6)) and replicated by the independent study series (P = 7 x 10(-5) and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

• Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer.

  Authors: Alexandros Daskalos, Georgios Nikolaidis, George Xinarianos, Paraskevi Savvari, Adrian Cassidy, Roubini Zakopoulou, Athanasios Kotsinas, Vassilis Gorgoulis, John K Field, Triantafillos Liloglou

  International journal of cancer. Journal international du cancer. 10/2008;

  LINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between globalLINE-1 and Alu elements are non-LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation-mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE-1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 x 10(-14) and 9.6 x 10(-7), respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot-spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 x 10(-5); Alu, p = 0.008). The reduction of the methylation index of LINE-1 and Alu following treatment of 3 lung cell lines with 5-aza-2'-deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non-small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy. (c) 2008 Wiley-Liss, Inc.

• A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25.

  Authors: Rayjean J Hung, James D McKay, Valerie Gaborieau, Paolo Boffetta, Mia Hashibe, David Zaridze, Anush Mukeria, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai [......] Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Fumihiko Matsuda, Helene Blanche, Ivo Gut, Simon Heath, Mark Lathrop, Paul Brennan

  Nature. 05/2008; 452(7187):633-7.

  Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide associationLung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.