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International Journal of Molecular... Jun 2020Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing... (Review)
Review
Malignant mesothelioma (MM) is mainly caused by air-born asbestos but genetic susceptibility is also suspected to be a risk factor. Recent studies suggest an increasing number of candidate genes that may predispose to MM besides the well-characterized BRCA1-associated protein-1 gene. The aim of this review is to summarize the most important studies on germline mutations for MM. A total of 860 publications were retrieved from Scopus, PubMed and Web of Science, of which 81 met the inclusion criteria and were consider for this review. More than 50% of the genes that are reported to predispose to MM are involved in DNA repair mechanisms, and the majority of them have a role in the homologous recombination pathway. Genetic alterations in tumor suppressor genes involved in chromatin, transcription and hypoxia regulation have also been described. Furthermore, we identified several single nucleotide polymorphisms (SNPs) that may promote MM tumorigenesis as a result of an asbestos-gene interaction, including SNPs in DNA repair, carcinogen detoxification and other genes previously associated with other malignancies. The identification of inherited mutations for MM and an understanding of the underlying pathways may allow early detection and prevention of malignancies in high-risk individuals and pave the way for targeted therapies.
Topics: Alleles; Animals; DNA Repair; Genetic Association Studies; Genetic Predisposition to Disease; Genetic Variation; Germ-Line Mutation; Humans; Mesothelioma, Malignant; Pedigree; Polymorphism, Single Nucleotide
PubMed: 32560575
DOI: 10.3390/ijms21124327 -
Annals of Global Health 2023The causal association between mesothelioma and asbestos exposure is conclusive, and many studies have proved that the trend in asbestos use is a strong predictor of the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The causal association between mesothelioma and asbestos exposure is conclusive, and many studies have proved that the trend in asbestos use is a strong predictor of the pattern in mesothelioma cases with an adequate latency time (generally around 30-40 years or more). Recently, a novel approach for predicting malignant pleural mesothelioma, based on asbestos consumption trend and using distributed non-linear models, has been applied.
OBJECTIVES
The purpose of this study is to analyse trends in asbestos consumption and malignant mesothelioma mortality in the major asbestos-user countries. Furthermore, we applied distributed non-linear models to estimate and compare epidemiological relationships between asbestos consumption and mesothelioma mortality across these countries.
METHODS
The study involves major asbestos-user countries in which historical asbestos consumption and mesothelioma mortality data are available. Data on asbestos consumption were derived from worldwide asbestos supply and mesothelioma mortality data from World Health Organization (WHO) mortality archives. A quasi-Poisson generalized linear model was used to model past asbestos exposure and male mesothelioma mortality rates in each country. Exposure-response associations have been modelled using distributed lag non-linear models.
FINDINGS AND CONCLUSIONS
According to the criteria defined above, we selected 18 countries with raw asbestos cumulative consumptions higher than two million tons in the period 1933-2012. Overall, a clear linear relationship can be observed between total consumption and total deaths for mesothelioma. Country-specific exposure, lag and age-response relationships were identified and common functions extracted by a meta-analysis procedure. Non-linear models appear suitable and flexible tools for investigating the association between mesothelioma mortality and asbestos consumption. There is a need to improve the global epidemiological surveillance of asbestos-related diseases, particularly mesothelioma mortality, and the absence of reliable data for some major asbestos-user countries is a real concern. A reliable assessment of mesothelioma mortality is a fundamental step towards increasing the awareness of related risks and the need of an international ban on asbestos.
Topics: Male; Humans; Mesothelioma, Malignant; Asbestos; Mesothelioma; World Health Organization; Linear Models; Lung Neoplasms; Pleural Neoplasms; Occupational Exposure
PubMed: 36819965
DOI: 10.5334/aogh.4012 -
Journal of Thoracic Oncology : Official... Mar 2022Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features...
INTRODUCTION
Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort.
METHODS
Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features.
RESULTS
A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗.
CONCLUSIONS
MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Peritoneal Neoplasms
PubMed: 34648949
DOI: 10.1016/j.jtho.2021.09.012 -
International Journal of Molecular... Mar 2020Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the... (Review)
Review
Malignant mesothelioma is an infrequent tumor that initiates from the mesothelial cells lining of body cavities. The great majority of mesotheliomas originate in the pleural cavity, while the remaining cases initiate in the peritoneal cavity, in the pericardial cavity or on the tunica vaginalis. Usually, mesotheliomas grow in a diffuse pattern and tend to enclose and compress the organs in the various body cavities. Mesothelioma incidence is increasing worldwide and still today, the prognosis is very poor, with a reported median survival of approximately one year from presentation. Thus, the development of alternative and more effective therapies is currently an urgent requirement. The aim of this review article was to describe recent findings about the anti-cancer activity of curcumin and some of its derivatives on mesotheliomas. The potential clinical implications of these findings are discussed.
Topics: Antineoplastic Agents; Curcumin; Humans; Mesothelioma, Malignant; Phytochemicals; Pleura; Pleural Neoplasms; Prognosis
PubMed: 32155978
DOI: 10.3390/ijms21051839 -
PloS One 2021Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease...
Human cytomegalovirus (HCMV) is a highly prevalent herpes virus which persists as a latent infection and has been detected in several different tumor types. HCMV disease is rare but may occur in high-risk settings, often manifesting as a pulmonary infection. To date HCMV has not been investigated in malignant pleural mesothelioma (MPM). In a consecutive case series of 144 MPM patients we evaluated two biomarkers of HCMV: IgG serostatus (defined as positive and negative) and DNAemia (>100 copies/mL of cell free HCMV DNA in serum). Approximately half of the MPM patient population was HCMV IgG seropositive (51%). HCMV DNAemia was highly prevalent (79%) in MPM and independent of IgG serostatus. DNAemia levels consistent with high level current infection (>1000 copies/mL serum) were present in 41% of patients. Neither IgG serostatus nor DNAemia were associated with patient survival. In tissues, we observed that HCMV DNA was present in 48% of tumors (n = 40) and only 29% of normal pleural tissue obtained from individuals without malignancy (n = 21). Our results suggest nearly half of MPM patients have a high level current HCMV infection at the time of treatment and that pleural tissue may be a reservoir for latent HCMV infection. These findings warrant further investigation to determine the full spectrum of pulmonary infections in MPM patients, and whether treatment for high level current HCMV infection may improve patient outcomes.
Topics: Aged; Antibodies, Viral; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Disease-Free Survival; Female; Humans; Immunoglobulin G; Male; Mesothelioma, Malignant; Middle Aged; Pleural Neoplasms; Pneumonia, Viral; Retrospective Studies; Survival Rate
PubMed: 34383785
DOI: 10.1371/journal.pone.0254136 -
Cell Death & Disease Apr 2021Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2...
Escape from programmed cell death is a hallmark of cancer. In this study, we investigated the anti-apoptotic mechanisms and explored the therapeutic potential of BCL-2 homology domain-3 (BH3) mimetics in malignant pleural mesothelioma (MPM), a lethal thoracic malignancy with an extreme dearth of treatment options. By implementing integrated analysis of functional genomic data of MPM cells and quantitative proteomics of patients' tumors, we identified BCL-X as an anti-apoptotic driver that is overexpressed and confers an oncogenic dependency in MPM. MPM cells harboring genetic alterations that inactivate the NF2/LATS1/2 signaling are associated with increased sensitivity to A-1155463, a BCL-X-selective BH3 mimetic. Importantly, BCL-X inhibition elicits protective autophagy, and concomitant blockade of BCL-X and autophagic machinery with A-1155463 and hydroxychloroquine (HCQ), the US Food and Drug Administration (FDA)-approved autophagy inhibitor, synergistically enhances anti-MPM effects in vitro and in vivo. Together, our work delineates the molecular basis underlying resistance to apoptosis and uncovers an evasive mechanism that limits response to BH3 mimetics in MPM, suggesting a novel strategy to target this aggressive disease.
Topics: Animals; Apoptosis; Autophagy; Humans; Male; Mesothelioma, Malignant; Mice; Mice, Inbred NOD; Mice, SCID; bcl-X Protein
PubMed: 33859162
DOI: 10.1038/s41419-021-03668-x -
Thoracic Cancer Jan 2021Malignant pleural mesothelioma (MPM) is a type of cancer originating from the pleura with high aggressiveness and poor prognosis. A timely diagnosis is crucial to... (Review)
Review
Malignant pleural mesothelioma (MPM) is a type of cancer originating from the pleura with high aggressiveness and poor prognosis. A timely diagnosis is crucial to improve its prognosis. Laboratory biomarkers have significant advantages of reduced invasiveness, low cost, and are observer-independent, and therefore represent a promising diagnostic tool for MPM. MicroRNA is a family of non-coding RNA that regulates gene expression at the post-transcriptional level. Accumulated studies showed that microRNA, either in tissue, circulating, and body fluid, has potential diagnostic value for various disorders. Here, we reviewed the diagnostic value of microRNA for MPM.
Topics: Humans; Mesothelioma, Malignant; MicroRNAs; Pleural Neoplasms
PubMed: 33225621
DOI: 10.1111/1759-7714.13746 -
MMWR. Morbidity and Mortality Weekly... May 2022Inhalation of asbestos fibers can cause malignant mesothelioma, a rapidly progressing and lethal cancer of the mesothelium, the thin layer of tissues surrounding...
Inhalation of asbestos fibers can cause malignant mesothelioma, a rapidly progressing and lethal cancer of the mesothelium, the thin layer of tissues surrounding internal organs in the chest and abdomen. Patients with malignant mesothelioma have a poor prognosis, with a median survival of 1 year from diagnosis. The estimated median interval from initial occupational asbestos exposure to death is 32 years (range = 13-70 years) (1). Occupational asbestos exposure is most often reported in men working in industries such as construction and manufacturing; however, women are also at risk for exposure to asbestos fibers, and limited data exist on longer-term trends in mesothelioma deaths among women. To characterize deaths associated with mesothelioma and temporal trends in mesothelioma mortality among women in the United States, CDC analyzed annual Multiple Cause of Death records from the National Vital Statistics System for 1999-2020, the most recent years for which complete data are available. The annual number of mesothelioma deaths among women increased significantly, from 489 in 1999 to 614 in 2020; however, the age-adjusted death rate per 1 million women declined significantly, from 4.83 in 1999 to 4.15 in 2020. The largest number of deaths was associated with the health care and social assistance industry (89; 15.7%) and homemaker occupation (129; 22.8%). Efforts to limit exposure to asbestos fibers, including among women, need to be maintained.
Topics: Asbestos; Data Collection; Female; Humans; Male; Mesothelioma; Mesothelioma, Malignant; Occupational Exposure; United States
PubMed: 35552365
DOI: 10.15585/mmwr.mm7119a1 -
International Journal of Molecular... Jul 2020For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in...
For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (, , , , (), , , , and ) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression ("passenger genes"). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of and significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As and deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.
Topics: Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Epithelium; Eukaryotic Initiation Factor-4G; Gene Expression Regulation, Neoplastic; Humans; Mesothelioma, Malignant; Pleural Neoplasms; Quinazolines; RNA, Small Interfering; Small Molecule Libraries; beta Karyopherins; ran GTP-Binding Protein
PubMed: 32659970
DOI: 10.3390/ijms21144856 -
Annals of Oncology : Official Journal... Feb 2022
Topics: Humans; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 34883215
DOI: 10.1016/j.annonc.2021.11.019