Risk Of Malignant Pleural Mesothelioma Research Articles

DHEA-S, Androstenedione, 17-β-estradiol signature as novel biomarkers for early prediction of risk of malignant pleural mesothelioma linked to asbestos-exposure: A preliminary investigation

17-β-estradiol, involved in mesothelioma pathogenesis, and its precursors were explored as potential biomarkers for the early diagnosis of mesothelioma. Using enzyme-linked immunosorbent assay(ELISA) for 17-β-estradiol and ultra-high performance liquid chromatography/tandem mass spectrometry(UHPLC-MS/MS) for 19 17-β-estradiol precursors, a comprehensive analysis of 20steroid hormones was conducted in the serum of mesothelioma patients(n=67), asbestos-exposed healthy subjects(n=39), and non-asbestos-exposed healthy subjects(n=35). Bioinformatics analysis explored three potential serum biomarkers: 17-β-estradiol, DHEA-S, and androstenedione. The results revealed significant differences in 17-β-estradiol levels between mesothelioma patients and both non-asbestos-exposed and asbestos-exposed healthy subjects. No significant variations in serum 17-β-estradiol levels were observed among mesothelioma patients at different stages, suggesting its potential as an early diagnostic marker. 17-β-estradiol levels were similar in mesothelioma patients with environmental and occupational asbestos exposure, while males with occupational asbestos exposure exhibited significantly higher levels of 17-β-estradiol compared to females. Significant reduction in androstenedione and an increase in DHEA-S were observed in asbestos-exposed individuals compared to non-asbestos-exposed individuals. The analysis of DHEA-S-androstenedione-17-β-estradiol signature score showed an increase in asbestos-exposed individuals and mesothelioma patients compared to non-asbestos-exposed individuals, and this score effectively distinguished between the groups. The Cancer Genome Atlas data was utilized to analyze the expression of 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 genes. The findings indicated that mesothelioma patients with elevated gene values for 5-α-reductase1 and hydroxysteroid-17β-dehydrogenase2 have a worse or better prognosis on overall survival, respectively. In conclusion, this study suggests 17-β-estradiol, DHEA-S, and androstenedione as biomarkers for mesothelioma risk and early diagnosis of mesothelioma in asbestos-exposed individuals, aiding timely intervention and improved care.

The risk of malignant pleural mesothelioma

The risk of malignant pleural mesothelioma Although the use of asbestos-containing building materials was banned in the UK in 1999, this carcinogenic mineral continues to be a serious health threat. Daniel J. Murphy from the University of Glasgow tells us more. The UK currently endures the highest incidence of Mesothelioma worldwide: 45 annual fatalities/million population; 1/212 male lifetime risk (1), making asbestos the leading cause of occupation-related mortality in the UK. (2) Although the use of asbestos-containing building materials was banned in the UK in 1999, an estimated 1.5 million UK buildings are thought to contain up to six million tons of asbestos – including 94% of hospitals, 80% of schools and 74% of university buildings. (3)

Identification of glycolysis genes signature for predicting prognosis in malignant pleural mesothelioma by bioinformatics and machine learning.

Glycolysis-related genes as prognostic markers in malignant pleural mesothelioma (MPM) is still unclear. We hope to explore the relationship between glycolytic pathway genes and MPM prognosis by constructing prognostic risk models through bioinformatics and machine learning. The authors screened the dataset GSE51024 from the GEO database for Gene set enrichment analysis (GSEA), and performed differentially expressed genes (DEGs) of glycolytic pathway gene sets. Then, Cox regression analysis was used to identify prognosis-associated glycolytic genes and establish a risk model. Further, the validity of the risk model was evaluated using the dataset GSE67487 in GEO database, and finally, a specimen classification model was constructed by support vector machine (SVM) and random forest (RF) to further screen prognostic genes. By DEGs, five glycolysis-related pathway gene sets (17 glycolytic genes) were identified to be highly expressed in MPM tumor tissues. Also 11 genes associated with MPM prognosis were identified in TCGA-MPM patients, and 6 (COL5A1, ALDH2, KIF20A, ADH1B, SDC1, VCAN) of them were included by Multi-factor COX analysis to construct a prognostic risk model for MPM patients, with Area under the ROC curve (AUC) was 0.830. Further, dataset GSE67487 also confirmed the validity of the risk model, with a significant difference in overall survival (OS) between the low-risk and high-risk groups (P < 0.05). The final machine learning screened the five prognostic genes with the highest risk of MPM, in order of importance, were ALDH2, KIF20A, COL5A1, ADH1B and SDC1. A risk model based on six glycolytic genes (ALDH2, KIF20A, COL5A1, ADH1B, SDC1, VCAN) can effectively predict the prognosis of MPM patients.

Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n=36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years=0.89; AUC 5-10 years=0.80; AUC >10 years=0.75; baseline AUC range=0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.

Application of deep learning models on whole slide images uncover new histological markers related to high-risk malignant pleural mesothelioma.

e13580 Background: Malignant Pleural mesothelioma (MPM) is a highly aggressive cancer of the pleural surface and represents 80-90% of mesothelioma diagnosis. MPM is broadly subclassified into three histological subgroups (epithelioid, sarcomatoid, biphasic), however tissue heterogeneity has resulted in diagnostic challenges and suboptimal patient care. There are currently no specific histological markers of high/low-risk MPM patients, which is critical in predicting patient prognosis. Methods: Owkin developed MesoNet, a deep learning model that predicts overall survival (OS) of MPM patients from whole slide images (WSI) and trained on the French MESOBANK and TCGA cohorts (Courtiol et al, 2019). In this study, we sought to validate MesoNet’s performance on an independent cohort of 127 WSI stained with haematoxylin/eosin from MPM patients collected at the University of Pittsburgh as part of the National Mesothelioma Virtual Bank (funding by U24OH009077). Patient demographics, survival data, expertly curated pathology annotations were also collected. Results: Our analyses showed that MesoNet predicted OS as risk score based on WSI, which validated high-risk MPM patients exhibited poorer OS, as compared to low-risk patients. Analyses on histological subtypes revealed sarcomatoid and biphasic patients were overrepresented in high-risk groups, as compared to epithelioid patients, which correlates with observed OS data. Notably, histological features associated with high-risk patients revealed tumor pleomorphism and anaplastic nuclear features, whereas low-risk tiles appear to be enriched in tumor infiltrating lymphocytes (TILs) with accompanying stromal proliferation and dense fibrosis. Conclusions: Collectively, our studies validate MesoNet performance on an independent cohort and identify new features related to MPM risk groups, which may inform future treatment stratification and personalization of immunotherapies.

Four Immune-Related Genes (FN1, UGCG, CHPF2 and THBS2) as Potential Diagnostic and Prognostic Biomarkers for Carbon Nanotube-Induced Mesothelioma

BackgroundMalignant pleural mesothelioma (MPM), a highly aggressive cancer, was mainly attributed to asbestos exposure. Carbon nanotubes (CNTs) share similar negative features to asbestos, provoking concerns about their contribution to MPM. This study was used to identify genes associated with CNT-induced MPM.MethodsMicroarray datasets were available in the Gene Expression Omnibus database. The limma method was used to identify differentially expressed genes (DEGs) in CNT-exposed MeT5A cells (GSE48855) or mice (GSE51636). Weighted correlation network analysis (WGCNA) and protein–protein interaction (PPI) network construction were conducted to screen hub DEGs. The mRNA expression levels of hub DEGs were validated on MPM samples of GSE51024, GSE2549 and GSE42977 datasets, and their diagnostic efficacy was determined by receiver operating characteristic curve analysis. The prognostic values of hub DEGs were assessed using online tools based on The Cancer Genome Atlas data. Their functions were annotated by Database for Annotation, Visualization and Integrated Discovery (DAVID) enrichment and correlation with immune cells and markers.ResultsWGCNA identified that two modules were associated with disease status. Thirty-one common DEGs in the GSE48855 and GSE51636 datasets were overlapped with the genes in these two modules. Twenty of them had a high degree centrality (≥4) in the PPI network. Four DEGs (FN1, fibronectin 1; UGCG, UDP-glucose ceramide glucosyltransferase; CHPF2, chondroitin polymerizing factor 2; and THBS2, thrombospondin 2) could predict the overall survival, and they were confirmed to be upregulated in MPM samples compared with controls. Also, they could effectively predict the MPM risk, with an overall accuracy of >0.9. DAVID analysis revealed FN1, CHPF2 and THBS2 functioned in cell-ECM interactions; UGCG influenced glycosphingolipid metabolism. All genes were positively associated with infiltrating levels of immune cells (macrophages or dendritic cells) and the expression of the dendritic cell marker (NRP1, neuropilin 1).ConclusionThese four immune-related genes represent potential biomarkers for monitoring CNT-induced MPM and predicting the prognosis.

Effect of Asbestos Consumption on Malignant Pleural Mesothelioma in Italy: Forecasts of Mortality up to 2040.

Simple SummaryAsbestos consumption figures could be used to construct epidemiological models to forecast the pleural mesothelioma mortality, although they are not frequently taken into consideration in this kind of analysis. Our purpose is to predict the future burden of pleural mesothelioma deaths in Italy until 2039 and to describe the exposure–response curve considering time lasted from the exposure start. Our results could be of interest to plan future needs of the Italian health system and to provide evidence on the consequences of asbestos exposures useful for countries in which this material is, at present, still used for productive activities.Statistical models used to forecast malignant pleural mesothelioma (MPM) trends often do not take into account historical asbestos consumption, possibly resulting in less accurate predictions of the future MPM death toll. We used the distributed lag non-linear model (DLNM) approach to predict future MPM cases in Italy until 2040, based on past asbestos consumption figures. Analyses were conducted using data on male MPM deaths (1970–2014) and annual asbestos consumption using data on domestic production, importation, and exportation. According to our model, the peak of MPM deaths is expected to occur in 2021 (1122 expected cases), with a subsequent decrease in mortality (344 MPM deaths in 2039). The exposure–response curve shows that relative risk (RR) of MPM increased almost linearly for lower levels of exposure but flattened at higher levels. The lag-specific RR grew until 30 years since exposure and decreased thereafter, suggesting that the most relevant contributions to the risk come from exposures which occurred 20–40 years before death. Our results show that the Italian MPM epidemic is approaching its peak and underline that the association between temporal trends of MPM and time since exposure to asbestos is not monotonic, suggesting a lesser role of remote exposures in the development of MPM than previously assumed.

New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment.

Simple SummaryOur study investigated DNA methylation differences in easily accessible white blood cells (WBCs) between malignant pleural mesothelioma (MPM) cases and asbestos-exposed cancer-free controls. A multiple regression model highlighted that the methylation level of two single CpGs (cg03546163 in FKBP5 and cg06633438 in MLLT1) are independent MPM markers. The epigenetic changes at the FKBP5 and MLLT1 genes were robustly associated with MPM in asbestos-exposed subjects. Interaction analyses showed that MPM cases and cancer-free controls showed DNAm differences which may be linked to asbestos exposure.Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = −0.09, 95% CI = −0.12|−0.06, p = 1.2 × 10−7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10−6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10−11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10−8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10−7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10−8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.

How can we use positron emission tomography/computed tomography more accurately for characterization of asbestos-related pleural thickening?

There is no consensus about the standardized uptake value maximum (SUVmax) cut-off value to characterize pleural thickening worldwide. Sometimes, this causes unnecessary invasive diagnostic procedures. Our first aim is to determine a cut-off value for SUVmax. Secondly, we try to answer the following question: If we use this cut-off value together with morphological parameters, can we differentiate benign thickening from malignant pleural mesothelioma (MPM) more accurately? Thirty-seven patients who underwent 2-deoxy-2-fluoro-D-glucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) before pleural biopsy were included the study. All of patients had histopathologically proven primary pleural disease. Their [18F]FDG-PET/CT imaging reports were re-assessed. If a patient's SUVmax or size of the thickening was not mentioned in the report, we calculated it with their [18F]FDG-PET/CT. Age, pleural effusion, size, and SUVmax were found to have a relationship with MPM. We found the size > 14 mm, and SUVmax > 4.0 as cut-off values for MPM. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for size > 14 mm were found to be 86.4%, 85.2%, 82.6%, 88.5%, respectively. For SUVmax > 4.0, sensitivity, specificity, PPV, NPV were 90.9%, 87.0%, 85.1%, 92.2%, respectively. If a patient has SUVmax > 4.0 and/or size > 14 mm, the risk of MPM is high. These patients should undergo biopsy. If a patient's SUVmax < 4.0, size < 14 mm and does not have pleural effusion, he/she has low risk for MPM. These patients can undergo the follow-up. If a patient's SUVmax < 4, size < 14, and has pleural effusion the MPM risk is approximately 4%. These patients can undergo biopsy/cytology/follow-up. Novel studies are needed for these patients.

Relationship between Pretreatment Serum Albumin Levels with the Risk of Malignant Pleural Mesothelioma

Background: Malignant Pleural Mesothelioma (MPM) is a very rare and aggressive form of cancer. Recently it was found that pretreatment Serum Albumin (SA), the main circulating protein in blood is a significant prognostic factor for MPM patients. The objective of this present article is to show the relationship between pretreatment Serum albumin (SA) levels with the risk of MPM. Methods: Generalized additive model (GAM), an advanced regression analysis method has been introduced here to find this mathematical relationship between the response variable (SA) and the cofactors. Results: The main determinates of SA are identified - asbestos exposure, hemoglobin, disease diagnosis status (patients having MPM) are the factors having significant association with SA, whereas duration of asbestos exposure, duration of disease symptoms, total protein (TP), Pleural lactic dehydrogenise (PLD), pleural protein (PP), pleural glucose (PG) and C-reactive protein (CRP) are the significant continuous variables for SA. The non-parametric estimation part of this model shows Lactate dehydrogenase (LDH) and Glucose level are the significant smoothing terms. Additionally it is also found that, second and third order interactions between cofactors are highly significant for SA. Conclusions: The findings of this present work can conclude that - serum albumin may play the role of a very significant prognostic factor for MPM disease and it has been established here through mathematical modeling. Few of the findings are already been exist in MPM research literature whereas some of the findings are completely new in the literature.

Association of two BRM promoter polymorphisms and smoking status with malignant pleural mesothelioma risk and prognosis.

Brahma (BRM), of the SWI/SNF complex, has two 6 to 7 bp insertion promoter polymorphisms (BRM-741/BRM-1321) that cause epigenetic BRM suppression, and are associated with risk of multiple cancers. BRM polymorphisms were genotyped in malignant pleural mesothelioma (MPM) cases and asbestos-exposed controls. Multivariable logistic regression (risk) and Cox regression (prognosis) were performed, including stratified analyses by smoking status to investigate the effect of polymorphisms on MPM risk and prognosis. Although there was no significant association overall between BRM-741/BRM-1321 and risk in patients with MPM, a differential effect by smoking status was observed (P-interaction < .001), where homozygous variants were protective (aOR of 0.18-0.28) in ever smokers, while never smokers had increased risk when carrying homozygous variants (aOR of 2.7-4.4). While there was no association between BRM polymorphisms and OS in ever-smokers, the aHR of carrying homozygous-variants of BRM-741, BRM-1321 or both were 4.0 to 8.6 in never-smokers when compared to wild-type carriers. Mechanistically, lower mRNA expression of BRM was associated with poorer general cancer prognosis. Electrophoretic mobility shift assays and chromatin immunoprecipitation experiments (ChIP) revealed high BRM insertion variant homology to MEF2 regulatory binding sites. ChIP experimentation confirmed MEF2 binding only occurs in the presence of insertion variants. DNA-affinity purification assays revealed YWHA scaffold proteins as vital to BRM mRNA expression. Never-smokers who carry BRM homozygous variants have an increased chance of developing MPM, which results in worse prognosis. In contrast, in ever-smokers, there may be a protective effect, with no difference in overall survival. Mechanisms for the interaction between BRM and smoking require further study.

Matrix metalloproteinases polymorphisms as baseline risk predictors in malignant pleural mesothelioma

Abstract Background Malignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure. Patients and methods The study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%–75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Results Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44–1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35–0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma. Conclusions The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.

Matrix Metalloproteinases Polymorphisms as Baseline Risk Predictors in Malignant Pleural Mesothelioma.

BackgroundMalignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure.Patients and methodsThe study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%–75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs).ResultsCarriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44–1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35–0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma.ConclusionsThe MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.

The Association Between the FTO rs9939609 Variant and Malignant Pleural Mesothelioma Risk: A Case-Control Study.

Despite the established link between malignant pleural mesothelioma (MPM) and asbestos exposure, genetic risk factors may play a key role in MPM pathogenesis. The rs9939609 polymorphism in the FTO gene has recently been implicated as a risk factor for some types of cancer, such as breast, pancreatic, and prostate cancers. FTO variation is associated with altered adipocytokine expression and oxidative stress inflammation, which may influence asbestos mediated-carcinogenesis. This is the first study to investigate a possible association between this polymorphism and MPM risk. FTO rs9939609 (T >A) genotypes were screened using a TaqMan® Genotyping Assay in a total of 235 Egyptian subjects (86 MPM patients versus 149 controls). The chi-square test and logistic regression were used to evaluate the association between the candidate variant and MPM risk using a case-control design. In the additive genetic model, the AT and AA genotypes were associated with a 2.48-fold (95% confidence intervals [CI] = 1.04-5.92, p = 0.04) and a 3.46-fold (95% CI = 0.99-12.01, p = 0.051) increase in the odds of developing MPM, respectively, when compared to the TT genotype after adjustment for body mass index, age, and gender. Additionally, in the dominant genetic model AT/AA genotypes were associated with a 2.63-fold increase in the odds of developing MPM (95% CI = 1.13-6.12, p = 0.025). The present study shows for the first time that rs9939609 polymorphism in the FTO gene may be a genetic risk factor for MPM. This study highlights the association of this genetic polymorphism with cancer susceptibility, and therefore, it should be investigated in various other populations, in relation to different types of cancer, and with larger sample sizes.

Estimating past inhalation exposure to asbestos: A tool for risk attribution and disease screening.

Late presentation is common in mesothelioma. Reliable assessment of past exposure to asbestos is a necessary first step for risk attribution and for the development of a future screening programme. Such a programme could maximise access to trials of novel therapies and would pave the way for development of novel chemoprophylaxis strategies. This paper describes a method for individual exposure reconstruction along with data from a validation study. The exposure assessment method uses only descriptive information about the circumstances of the work that could be obtained from questioning the worker. The assessment is based on the tasks carried out and includes parameters for substance emission potential, activity emission potential, the effectiveness of any local control measures, passive emission, the fractional time the asbestos source is active and the efficiency of any respiratory protection worn. There was a good association between the estimated and measured exposure levels. Pearson's correlation coefficient between the log-transformed measurements and estimates from the model was 0.86, and 95% of the estimated individual values were within about a factor of ten of the associated measured value. The method described would be suitable for pre-selecting individuals at high risk of malignant pleural mesothelioma for screening using appropriate tools and/or enrolment in clinical trials of chemo-prophylaxis. This method is of potential clinical value in developing novel treatment approaches for mesothelioma. Pilot studies to test this approach are urgently needed.

Increased risk of mesothelioma and lung cancer among workers exposed to asbestos who could require an anticipated retirement

to assess the association among malignant pleural mesothelioma (MPM) and lung cancer (LC) among workers who have been exposed to asbestos and have or not have required an anticipated leave from work, a possibility offered by the 1992 law banning asbestos in Italy, in the framework of the health surveillance programmes on going in the Veneto Region (Northern Italy). a cohort of asbestos workers derived from the rosters of selected factories and alive in 1992, followed from 1992 to 2012.MPM cases have been identified through the Regional Mesothelioma Registry, while LC cases through a link with the Regional Cancer Registry, hospital discharges, and death certificates. Risks related to asbestos exposure were calculated by mixed effects Poisson regression model. the risk of MPM and LC increases at any additional duration of work, up to very high values for long term durations of work for MPM, and up to a three fold increase for LC. Early retirements have been requested by a fraction only in the position of submitting it. subjects who have been exposed to asbestos should be the target of a post-occupational surveillance, and further work is suggested to identify subjects at high risk of LC because of smoking habits and more heavy exposure to asbestos, in order to develop programmes for primary and secondary cancer prevention.

Emerging evidence that the ban on asbestos use is reducing the occurrence of pleural mesothelioma in Sweden.

Aims: Several countries have banned the use of asbestos. The future health impacts of previous use have been modeled but there are to our knowledge no convincing studies showing a decreased occurrence of asbestos-related diseases due to a ban. The aim of our study was to estimate the effects of the ban and other measures to decrease the use of asbestos in Sweden. Methods: The effect was measured through comparing the incidence of pleural malignant mesothelioma in birth cohorts who started to work before and after the decrease in the use of asbestos, i.e. in mid-1970s. Cases were identified through the Swedish Cancer Registry and the analysis was restricted to persons born in Sweden. Results: Men and women born 1955–79 had a decreased risk of malignant pleural mesothelioma compared to men and women born 1940–49 (RR 0.16, 95% CI 0.11–0.25; and RR 0.47, 95% CI 0.23–0.97 respectively). The decreased use of asbestos prevented each year about 10 cases in men and two cases in women below the age of 57 years in 2012. Conclusions: The ban and decreased use of asbestos in Sweden can be measured today in birth cohorts that started their working career after the decrease.

Gene-asbestos interaction in malignant pleural mesothelioma susceptibility.

Asbestos exposure is the main risk factor for malignant pleural mesothelioma (MPM), a rare aggressive tumor. Nevertheless, on average less than 10% of subjects highly exposed to asbestos develop MPM, suggesting the possible involvement of other risk factors. To identify the genetic factors that may modulate the risk of MPM, we conducted a gene-environment interaction analysis including asbestos exposure and 15 single nucleotide polymorphisms (SNPs) previously identified through a genome-wide association study on Italian subjects. In the present study, we assessed gene-asbestos interaction on MPM risk using relative excess risk due to interaction and synergy index for additive interaction and V index for multiplicative interaction. Generalized multifactor dimensionality reduction (GMDR) analyses were also performed. Positive deviation from additivity was found for six SNPs (rs1508805, rs2501618, rs4701085, rs4290865, rs10519201, rs763271), and four of them (rs1508805, rs2501618, rs4701085, rs10519201) deviated also from multiplicative models. However, after Bonferroni correction, deviation from multiplicative model was still significant for rs1508805 and rs4701085 only. GMDR analysis showed a strong MPM risk due to asbestos exposure and suggested a possible synergistic effect between asbestos exposure and rs1508805, rs2501618 and rs5756444. Our results suggested that gene-asbestos interaction may play an additional role on MPM susceptibility, given that asbestos exposure appears as the main risk factor.

Abstract 437: Novel function of the BAP1 nuclear deubiquitinase in the non-homologous end joining (NHEJ) pathway of double strand DNA repair

Abstract Background- The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of malignant pleural mesothelioma (MPM) and uveal melanoma and in subsets of sporadic cases of these cancers, as well as in clear cell renal carcinoma and intrahepatic cholangiocarcinoma. Methods and Results- We found that BAP1 knockdown is associated with increased DNA damage and that this effect of BAP1 knockdown is further enhanced by both X-irradiation and concomitant DNA-PKcs inhibitor II treatment in normal human mesenchymal stem cells and the MPM cell line H-Meso. A BAP1 mutant deficient in deubiquitinase activity is also associated with increased DNA damage in the H-Meso cells. Interactional total peptide (ITOP) analysis based on proteins identified by Liquid Chromatography coupled to tandem Mass Spectrometry (LC-MS/MS) of BAP1 protein complexes in H-Meso MPM cells and 293T cells identified known binding partners [HCF1, ASXL2, H2A] as well as possible novel interaction partners, notably PRKDC which encodes the catalytic subunit of the DNA-dependent protein kinase (DNA-PKcs) and functions with the Ku70/Ku80 heterodimer in the non-homologous end joining (NHEJ) pathway of DNA repair. Double stranded DNA damage resulted in prominent nuclear expression of BAP1 protein in H-Meso cells and phosphorylation of BAP1 at Serine 395. Overexpression of dominant negative BAP1 C91W mutant in MPM cells caused instability of DNA-PKcs. Although strong polyubiquitination of DNA-PKcs was observed upon DNA damage in MPM cells expressing BAP1 C91W, this polyubiquitination was not observed in the presence of wild type BAP1. A plasmid-based NHEJ assay also confirmed a significant effect of BAP1 on NHEJ activity. Conclusion- Functional complexes between BAP1 and the NHEJ family components point to a novel role in DNA repair and may shed light on BAP1's role as an important tumor suppressor Citation Format: Tatsuo Ito, Shigehisa Kitano, Hediye Erdjument-Bromage, Marc Ladanyi. Novel function of the BAP1 nuclear deubiquitinase in the non-homologous end joining (NHEJ) pathway of double strand DNA repair. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2014-437

Thoracic Ultra Sound (TUS) integrated approach for FNAB‐US guided diagnosis and for monitoring environmental exposed subjects at risk of malignant pleural mesothelioma (MPM) and lung cancer (LC). Overview and preliminary report of TUS monitoring and screening approach. (LB498)

Thoracic Ultrasound (TUS) Image‐guided sampling of thickened pleura and of lung nodules is a valuable approach in patients with lung cancer (LC) and malignant pleural mesothelioma (MPM); moreover, we monitor by TUS imaging patients with occupational or environmental risk of MPM and LC addressing them more selectively to high resolution computerized tomography (HRCT), also with contrast CT for a further definition. A retrospective analysis of TUS imaging and of the diagnostic yield and complications of TUS‐guided fine needle aspirate biopsies (FNAB) was done. Results: the records of 133 patients with MPM and 801 patients with LC were analyzed. In 55/133 MPM and in 801/801 patients with LC (2008‐2013)TUS‐guided FNAB was performed using 20 G needles and a US transducer with a central passage. The specimens were of satisfactory size (length 1.0‐2.5 cm); in 20/801 LC patients a second FNAB was needed for further immunohistochemistry specimens. No significant complication was observed; 5 patient had partial pneumothorax following biopsies. The TUS signs observed in histologically confirmed MPM were irregular thickening of pleural line (above 5.0 mm) with associated micro‐nodules (5‐10 mm); a lower percentage showed plaque nodulations (5‐10 mm), all with slight or relevant pleural effusion. Patients at risk, without MPM/LG, under TUS monitoring, have irregular thickening of pleural line (above 3.0 mm), with associated micro‐nodules (2‐4 mm); a lower percentage have plaque nodulations (4‐7 mm). These early signs of lung involvement in subjects exposed to asbestos were observed in the absence of CXR findings, and with subsequent HRCT evidence without need of FNAB. Conclusion: TUS guided FNAB is a safe, affordable and reliable tool for the diagnosis of MPM and LC patients, provided that an adequate expertise of the operator and of the pathologist is available.TUS is currently used in our Institution as a complementary tool for screening patients with environmental or occupational risk for MPM and LC. They are preliminarily assessed by HRCT and TUS; this last is scheduled every six months thereafter. Diagnosing patients with pleural thickenings and/or subpleural nodes suspect for MPM is used to address to HRCT and/or contrast CT with the prospect of further focused indications to ultrasound‐guided FNAB.$graphic_00251AF2‐7D54‐4C2E‐BAF9‐980B59FD83CB$