Impact of an asbestos cement factory on mesothelioma incidence in a community in Italy

Abstract Background Broni is a small town (9000 inhabitants) in the province of Pavia, Lombardy, north-west Italy, where the second largest Italian asbestos cement factory (Fibronit) was in operation between 1932 and 1993. Based on Lombardy Mesothelioma Registry (RML) data (2000–2011), we previously showed a high impact of asbestos exposure on malignant mesothelioma (MM) incidence among Fibronit workers, their families, and people living in Broni and in the nearby town of Stradella (11,000 residents). Given the great concern of the community, we have recently updated the data regarding 5 more years (2012–2016). Methods From the RML database we extracted subjects who ever worked in Fibronit, their family members, ever residents in Broni, and subjects living in Stradella and nearby towns at the time of diagnosis. For each type of exposure we calculated standardized incidence ratios (SIR = observed/expected cases). Results In the period 2000–2016 we registered 56 cases (2.52 expected, SIR = 22.2), 49 men (41 pleural, 8 peritoneal MM), 7 women (5 pleural, 2 peritoneal MM) with past occupational exposure in Fibronit. Among subjects never occupationally exposed and never exposed to extra-occupational sources unrelated to Fibronit, we counted 39 cases (4.24 expected, SIR = 9.2), 10 men (all pleural MM), 29 women (28 pleural, 1 peritoneal MM) in Fibronit workers' families, 91 pleural mesothelioma cases (7.43 expected, SIR = 12.2, 31 men, 60 women), ever residents in Broni, and 25 pleural mesothelioma cases (3.05 expected, SIR = 8.2, 6 men, 19 women) living in Stradella at the time of diagnosis. The overall number of excess cases was about 194 (211 against 17.24 expected). In the remaining adjacent (No. 8) and surrounding (No. 17) municipalities (32,000 people) there were 7 cases (1 men, 6 women, 8.85 expected). Conclusion The mesothelioma burden related to the asbestos cement factory is still high on factory workers, their families, and residents in Broni and Stradella towns

Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival

Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure.We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e.g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers.Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers

Neonatal Thyroid Function in Seveso 25 Years after Maternal Exposure to Dioxin

Andrea Baccarelli and colleagues show that maternal exposure to a dioxin following the industrial accident in Seveso, Italy in 1976 is associated with modified neonatal thyroid function even many years later

Environment And Genetics in Lung cancer Etiology (EAGLE) study: An integrative population-based case-control study of lung cancer

Background: Lung cancer is the leading cause of cancer mortality worldwide. Tobacco smoking is its primary cause, and yet the precise molecular alterations induced by smoking in lung tissue that lead to lung cancer and impact survival have remained obscure. A new framework of research is needed to address the challenges offered by this complex disease. Methods/Design: We designed a large population-based case-control study that combines a traditional molecular epidemiology design with a more integrative approach to investigate the dynamic process that begins with smoking initiation, proceeds through dependency/smoking persistence, continues with lung cancer development and ends with progression to disseminated disease or response to therapy and survival. The study allows the integration of data from multiple sources in the same subjects (risk factors, germline variation, genomic alterations in tumors, and clinical endpoints) to tackle the disease etiology from different angles. Before beginning the study, we conducted a phone survey and pilot investigations to identify the best approach to ensure an acceptable participation in the study from cases and controls. Between 2002 and 2005, we enrolled 2101 incident primary lung cancer cases and 2120 population controls, with 86.6% and 72.4% participation rate, respectively, from a catchment area including 216 municipalities in the Lombardy region of Italy. Lung cancer cases were enrolled in 13 hospitals and population controls were randomly sampled from the area to match the cases by age, gender and residence. Detailed epidemiological information and biospecimens were collected from each participant, and clinical data and tissue specimens from the cases. Collection of follow-up data on treatment and survival is ongoing. Discussion: EAGLE is a new population-based case-control study that explores the full spectrum of lung cancer etiology, from smoking addiction to lung cancer outcome, through examination of epidemiological, molecular, and clinical data. We have provided a detailed description of the study design, field activities, management, and opportunities for research following this integrative approach, which allows a sharper and more comprehensive vision of the complex nature of this disease. The study is poised to accelerate the emergence of new preventive and therapeutic strategies with potentially enormous impact on public health

Alcohol and lung cancer risk among never smokers: A pooled analysis from the international lung cancer consortium and the SYNERGY study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/1/ijc30618-sup-0001-supptables.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/2/ijc30618_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136447/3/ijc30618.pd

Protein-altering germline mutations implicate novel genes related to lung cancer development

Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 × 10−15) and replication (adjusted OR = 2.93, P = 2.22 × 10−3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 × 10−22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk

Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer

Descriptive epidemiology of somatising tendency: findings from the CUPID study.

Somatising tendency, defined as a predisposition to worry about common somatic symptoms, is importantly associated with various aspects of health and health-related behaviour, including musculoskeletal pain and associated disability. To explore its epidemiological characteristics, and how it can be specified most efficiently, we analysed data from an international longitudinal study. A baseline questionnaire, which included questions from the Brief Symptom Inventory about seven common symptoms, was completed by 12,072 participants aged 20-59 from 46 occupational groups in 18 countries (response rate 70%). The seven symptoms were all mutually associated (odds ratios for pairwise associations 3.4 to 9.3), and each contributed to a measure of somatising tendency that exhibited an exposure-response relationship both with multi-site pain (prevalence rate ratios up to six), and also with sickness absence for non-musculoskeletal reasons. In most participants, the level of somatising tendency was little changed when reassessed after a mean interval of 14 months (75% having a change of 0 or 1 in their symptom count), although the specific symptoms reported at follow-up often differed from those at baseline. Somatising tendency was more common in women than men, especially at older ages, and varied markedly across the 46 occupational groups studied, with higher rates in South and Central America. It was weakly associated with smoking, but not with level of education. Our study supports the use of questions from the Brief Symptom Inventory as a method for measuring somatising tendency, and suggests that in adults of working age, it is a fairly stable trait