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Malignant mesothelioma is a rare highly invasive tumour originating from the mesothelial cells of the pleura, peritoneum and pericardium. Malignant pleural mesothelioma (MPM) is the most common type in all malignant mesothelioma. The onset of MPM is associated with exposure to asbestos and it can have an incubation period of up to 40 years. The incidence of MPM has been increasing worldwide in recent years, so more attention has been focused on its diagnosis, treatment and prognosis. Activating mutations, amplifications and fusions/rearrangements of the anaplastic lymphoma kinase receptor tyrosine kinase ( ALK ) gene are commonly seen in patients with non-small cell lung cancer. However, it is rare in MPM. This current case report describes a female patient with advanced MPM with an ALK gene fusion mutation. In this particular case, treatment with crizotinib demonstrated some initial efficacy, which suggests that this might be a promising strategy for patients with advanced MPM with an ALK gene mutation. This required further research and evaluation in the future., Competing Interests: Declaration of conflicting interestThe authors declare that there are no conflicts of interest.

Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery. This analysis has allowed us to identify with high confidence numerous known and novel gene dependencies that are surprisingly highly enriched for non-oncogenic pathways involved in response to various stress stimuli, in particular DNA damage and transcriptional dysregulation. By integrating genomic analysis with a series of in vitro and in vivo functional studies, we validate and prioritize several non-oncogene addictions conferred by CDK7, CHK1, HDAC3, RAD51, TPX2, and UBA1 as targetable vulnerabilities, revealing previously unappreciated aspects of PM biology. Our findings support the growing consensus that stress-responsive non-oncogenic signaling plays a key role in the initiation and progression of PM and provide a functional blueprint for the development of unprecedented targeted therapies to combat this formidable disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a poor prognosis and the identification of novel druggable targets is urgently needed. In previous work, we identified 15 deregulated genes highly expressed in MPM tissues and correlated with a poor prognosis. Here, we validated these findings on an independent dataset of 211 MPM patients (EGA, EGAD00001001915) and on a panel of MPM cell lines. Furthermore, we carried out in vitro gene silencing followed by proliferation, cytotoxicity, caspase, and migration assays to define whether these targets could be cancer-driver genes. We ended up with three novel candidates (i.e., BAG2, MAD2L1, and MDK), whose encoded proteins could be exploited as druggable targets. Moreover, of novelty, immunohistochemistry analysis on tissues revealed that the overexpression of BAG2 and MAD2L1 could differentiate MPM from RMP patients. Furthermore, when we tested Neratinib (an inhibitor of MAD2L1) and iMDK (an inhibitor of MDK) we found that they are effective on MPM cells, in part phenocopying the effects of MAD2L1 and MDK gene silencing. In summary, in the present work, we report that BAG2, MAD2L1, and MDK are bona fide cancer-driver genes for MPM worth of further studies., Competing Interests: Competing interests The authors declare no competing interests. Ethics approval and consent to participate The collection and analysis of human tissue samples were conducted in accordance with the Declaration of Helsinki and with approvals by the Ethical Committee of the Capital Region of Denmark (Protocol No. H32011135-57379) and the Danish Data Protection Agency (Protocol No. DT2016414917), as previously described [15]. Additionally, the Danish Registry for Use of Tissue was checked to ensure that patients included in the study had not refused the usage of their tissue samples for research purposes., (© 2024. The Author(s).)

This review delves into the intricate landscape of pleural mesothelioma (PM), emphasizing the need for nuanced therapeutic strategies. While platinum-based chemotherapy remains a cornerstone, the advent of immune checkpoint inhibitors (ICIs), notably through the Checkmate 743 trial, has reshaped treatment paradigms. Challenges persist due to patient heterogeneity and a lack of specific biomarkers. Targeting genotypic and phenotypic alterations emerges as a promising avenue, demanding precision oncology in this rare disease. CDKN2A loss, prevalent in PM, may respond to CDK4/6 inhibitors. Defects in MMR and HR suggest tailored approaches with ICI or PARP inhibitors, respectively. Ongoing trials explore novel inhibitors and promising targets like mesothelin. Implementing these strategies requires overcoming challenges in patient selection, combination therapies, biomarker identification, and cost considerations. Collaboration is crucial for transforming these insights into impactful clinical interventions, heralding the era of personalized and precision medicine for PM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving the understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA sequencing (scRNA-seq) to de novo identify 54 expression programs and construct a comprehensive cellular catalog of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Across cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, and cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A:HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases. Significance: This manuscript presents the first single-cell RNA sequencing atlas of PM tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM., (©2024 American Association for Cancer Research.)

Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM., Competing Interests: Declaration of interests A patent application about mesothelioma gene therapy has been filed., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Four primary extraskeletal osteosarcomas of the pleura are presented. The patients were men between the ages of 63 and 78 years (average: 70.5 years) who presented with symptoms of chest pain, cough, and shortness of breath. Diagnostic imaging showed variably calcified, pleural-based masses and/or diffuse pleural thickening, clinically mimicking mesothelioma. Thoracoscopic surgical material was obtained for histopathological diagnosis. Histological findings showed the presence of a neoplastic spindle cell proliferation composed of fusiform cells with scant cytoplasm, elongated nuclei and inconspicuous nucleoli. Mitotic activity was easily identified. Additionally, all tumors showed extensive osseous differentiation in the form of osteoid matrix production; one tumor demonstrated additional chondrosarcomatous elements and another showed focal myxoid changes. Immunohistochemical analysis revealed that the tumor cells were uniformly negative for a wide variety of antibodies, including keratin AE1/AE3, keratin 5/6, D2-40, EMA, calretinin, WT-1, BerEP4, and HEG1; BAP1 was retained in all cases. In addition, fluorescence in situ hybridization for CDKN2A (p16) was negative for homozygous deletion in all tumors. Clinical follow-up showed that one patient had died 8 months after diagnosis and one had remained alive with short post-diagnostic follow-up. The tumors herein described highlight a challenging issue in the separation of mesothelioma with heterologous elements from true osteosarcomas of pleural origin. We propose that a diagnosis of extraskeletal osteosarcoma of the pleura is rendered for tumors with malignant osseous and/or cartilaginous differentiation in which comprehensive immunohistochemical studies and FISH analysis have failed to provide support for a diagnosis of mesothelioma with heterologous elements., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the effects of long-term exposure to chrysotile and crocidolite on miRNAs and epithelial mesenchymal transformation (EMT) -related gene expression in human pleural mesothelial cells. Methods: In November 2020, fluorescence quantitative polymerase chain reaction (RT-qPCR) was used to detect the expressions of EMT-related genes in human pleural mesothelioma cells (NCl-H2052 cells, NCl-H2452 cells) and human normal mesothelial cells (Met-5A cells). MiRNAs with abnormal expression in human pleural mesothelioma cells were screened out from the previous miRNA chip data of research group, and target genes of differentially expressed miRNAs were predicted using miRWalk database (http: //mirwalk.umm.uni-heidelberg.de). RT-qPCR was used to verify the abnormal expression of EMT-related miRNAs in cell lines. Met-5A cells were treated with 5μg/cm(2) chrysotile and crocidolite respectively for 48 h a time, once a week and a total of 10 times. Chrysotile group, crocidolite group and control group were set up. And the control group was added with the same volume of PBS. The expression changes of EMT-related genes and abnormal expression miRNAs in each group were detected by RT-qPCR. The differences among the groups were compared by one-way ANOVA, and the differences between the control group and the experimental group were compared by dunnet- t test. Results: Compared with Met-5A cells, the expression levels of Vimentin and Twist genes were increased, and the expression level of E-cadherin genes was decreased in NCl-H2052 cells and NCl-H2452 cells ( P <0.001). Target genes of miRNAs with abnormal expression in miRNA chip were predicted, and the results showed four abnormally expressed miRNAs associated with EMT and verified the expression of these four miRNAs in the cell lines. Compared with Met-5A cells, the expression level of hsa-miR-155-5p was increased in NCl-H2052 cells and NCl-H2452 cells, the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased in NCl-H2052 cells and NCl-H2452 cells ( P <0.001), which was consistent with the results of chip analysis. After exposure of Met-5A cells, it was found that compared with the control group, the expression levels of Vimentin and Twist genes, hsa-miR-155-5p, hsa-miR-34b-5p and hsa-miR-34c-5p in the crocidolite group were increased, while the expression level of E-cadherin gene was decreased ( P <0.05). Compared with the control group, the expression levels of Vimentin, Twist and E-cadherin genes in chrysotile group were increased, while the expression levels of hsa-miR-34b-5p, hsa-miR-34c-5p and hsa-miR-28-5p were decreased ( P <0.05) . Conclusion: Long-term exposure to chrysotile and crocidolite could cause Met-5A cells to produce miRNAs and EMT-related gene expression changes similar to mesothelioma cells.

Background: First- and second-generation anti-epithelial growth factor receptor tyrosine kinase inhibitors have shown great efficacy in the treatment of advanced adenocarcinoma with epithelial growth factor receptor mutations, but this efficacy is limited by certain resistance mechanisms, in particular the T790M mutation, which must be screened before second-line treatment with osimertinib is indicated. The search for this mutation is sometimes difficult, especially in cases of intracranial relapse, through this case report we attempt to discuss the possibility of initiating treatment with osimertinib despite an unknown T790M mutation in such situation., Case Report: We present the case of a 70-year-old Moroccan male patient diagnosed with non-small cell lung carcinoma initially metastatic to the pleura with an epithelial growth factor receptor mutation who received gefitinib in first line with a complete response, he subsequently presented with cerebral oligo-progression with extra cranial stability. The patient was started on osimertinib with unknown T790M status, as it was impossible to perform a cerebral biopsy, the evolution was characterized by a partial response followed by stereotactic radiotherapy then a complete response for 2 years., Conclusion: We can discuss osimertinib as an option for patients with stage IV non-small cell lung cancer with brain oligo-progression on prior tyrosine kinase inhibitors and unknown T790M status, further studies are needed in this area., (© 2024. The Author(s).)

Background: Mesothelioma is a rare and aggressive malignant neoplasm arising from mesothelial cells, which occasionally manifests recurrent fusions. EWSR1/FUS-CREB, YY1, MAP3K8, NR4A3, and ALK-rearranged proliferations have been reported in limited series with no clear histological or clinical correlations, limiting clinicians' ability to assess prognosis and integrate these new entities into therapeutic decisions. The aim of this study was to better characterize these rearranged proliferations histologically, molecularly, and clinically., Methods: Clinical, pathological, and comprehensive transcriptome and mutation data were collected for each case., Results: A total of 41 tumors were included, encompassing 7 ALK, 10 MAP3K8, 4 NR4A3, 8 ESWR1/FUS::ATF1, 8 EWSR1::YY1, and 4 SUFU-fused cases. We found a female predominance, except for cases harboring NR4A3 and SUFU; and most patients were around 60 years of age, but those harboring ALK or EWSR1/FUS::ATF1 gene fusions were younger. Each group exhibited distinct histological, immunohistochemical, molecular features, and oncological courses. Specifically, MAP3K8 and ALK presented PAX8+ papillary proliferations, ESWR1/FUS::ATF1 and EWSR1::YY1 displayed angiomatoid fibrous histiocytoma-like patterns, while SUFU showcased 'tissue culture'-like spindle cell proliferation. Poor prognosis factors were the pleural site, male sex, Ki67 ≥10%, and ESWR1/FUS::ATF1 or SUFU gene fusions., Conclusions: This study significantly broadens the spectrum of mesothelial tumors associated with fusions, offering insight into novel epithelioid (mesothelial) proliferations with distinctive histological appearances, molecular profiles, and prognoses to guide adapted treatments for patients., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Fluoroedenite-induced pleural mesothelioma (FE-induced-PM) is a rare and small subset of PM that shares with its asbestos-induced counterpart the same aggressive biological behavior and poor prognosis, but that differs from it from a pathogenetic point of view as it is associated with exposure to fluoroedenite, a carcinogenic agent that shows similarities with tremolite amphibolic asbestos fibers. Although it has been demonstrated that asbestos-induced PMs frequently harbor CDKN2A homozygous deletion and that the immunohistochemical loss of MTAP may represent a cheap and reliable surrogate marker for this molecular alteration, little is known about the molecular landscape and the reliability of MTAP immunohistochemistry in this peculiar subset of PM. The study herein presented investigated the prevalence of CDKN2A homozygous deletion and its concordance with MTAP immunohistochemical status on a cohort of 10 cases of FE-induced-PM from patients with environmental exposure to FE fibers, who were residents in the small town of Biancavilla (Sicily, Italy) or nearby areas. CDKN2A homozygous deletions were found in 3 out of 10 cases (30%) and all these cases showed concomitant cytoplasmic loss of MTAP with a concordance rate of 100%. Despite the relatively low number of cases included in our series, MTAP immunohistochemistry seemed to represent a reliable immunohistochemical surrogate marker of CDKNA homozygous deletion even in this subset of PMs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Purpose: Diffuse pleural mesotheliomas (DPM) with genomic near-haploidization (GNH) represent a novel subtype first recognized by The Cancer Genome Atlas project; however, its clinicopathologic and molecular features remain poorly defined., Experimental Design: We analyzed clinical genomic profiling data from 290 patients with DPM using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. Allele-specific copy number analysis was performed using the Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) algorithm., Results: A total of 210 patients were evaluable for loss of heterozygosity (LOH) analysis using FACETS from MSK-IMPACT tumor:normal sequencing data. In this cohort, GNH, defined as LOH across >80% of the genome, was detected in 10 cases (4.8%). Compared with non-GNH tumors, GNH DPMs were associated with younger age and less frequent self-reported history of occupational asbestos exposure. Histologically, GNH DPMs were enriched in biphasic subtype (80% vs. 14.5%) and showed abundant tumor-infiltrating lymphocytes (TILs). Genomic analysis revealed a higher frequency of TP53 alterations, whereas SETDB1 mutations were present in nearly all and only in this subset. The clinicopathologic and molecular findings were further validated in a separate cohort. Despite the younger age, patients with GNH DPMs had a shorter overall survival (10.9 vs. 25.4 months, P = 0.004); the poor prognostic impact of GNH remained significant after controlling for biphasic histology. Of three patients with GNH DPMs who received immune checkpoint blockade, two achieved a clinician-assessed partial response., Conclusions: GNH defines an aggressive subtype of mainly biphasic DPMs in younger patients with recurrent alterations in SETDB1 and TP53. The enrichment in biphasic histology and TILs, together with our preliminary immune checkpoint blockade response data and anecdotal clinical trial data, suggests that further evaluation of immunotherapy may be warranted in this subset., (©2024 American Association for Cancer Research.)

Malignant pleural mesothelioma is a rare and lethal cancer caused by exposure to asbestos. The highly inflammatory environment caused by fibers accumulation forces cells to undergo profound adaptation to gain survival advantages. Prioritizing the synthesis of essential transcripts is an efficient mechanism coordinated by multiple molecules, including long non-coding RNAs. Enhancing the knowledge about these mechanisms is an essential weapon in combating mesothelioma. Linc00941 correlates to bad prognosis in various cancers, but it is reported to partake in distinct and apparently irreconcilable processes. In this work, we report that linc00941 supports the survival and aggressiveness of mesothelioma cells by influencing protein synthesis and ribosome biogenesis. Linc00941 binds to the translation initiation factor eIF4G, promoting the selective protein synthesis of cMYC, which, in turn, enhances the expression of key genes involved in translation. We analyzed a retrospective cohort of 97 mesothelioma patients' samples from our institution, revealing that linc00941 expression strongly correlates with reduced survival probability. This discovery clarifies linc00941's role in mesothelioma and proposes a unified mechanism of action for this lncRNA involving the selective translation of essential oncogenes, reconciling the discrepancies about its function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pleural mesothelioma (PM) is a highly aggressive tumor that is caused by asbestos exposure and lacks effective therapeutic regimens. Current procedures for PM diagnosis are invasive and can take a long time to reach a definitive result. Small extracellular vesicles (sEVs) have been identified as important communicators between tumor cells and their microenvironment via their cargo including circular RNAs (circRNAs). CircRNAs are thermodynamically stable, highly conserved, and have been found to be dysregulated in cancer. This study aimed to identify potential biomarkers for PM diagnosis by investigating the expression of specific circRNA gene pattern (hsa&#95;circ&#95;0007386) in cells and sEVs using digital polymerase chain reaction (dPCR). For this reason, 5 PM, 14 non-PM, and one normal mesothelial cell line were cultured. The sEV was isolated from the cells using the gold standard ultracentrifuge method. The RNA was extracted from both cells and sEVs, cDNA was synthesized, and dPCR was run. Results showed that hsa&#95;circ&#95;0007386 was significantly overexpressed in PM cell lines and sEVs compared to non-PM and normal mesothelial cell lines ( p < 0.0001). The upregulation of hsa&#95;circ&#95;0007386 in PM highlights its potential as a diagnostic biomarker. This study underscores the importance and potential of circRNAs and sEVs as cancer diagnostic tools.

Background: In Dayao County, Chuxiong Yi Autonomous Prefecture, Yunnan Province, Southwest China, 5% of the surface is scattered with blue asbestos, which has a high incidence of pleural mesothelioma (PMe). Simian virus 40 (SV40) is a small circular double-stranded DNA polyomavirus that can cause malignant transformation of normal cells of various human and animal tissue types and promote tumor growth. In this study, we investigate whether oncogenic SV40 is associated with the occurrence of PMe in the crocidolite-contaminated area of Dayao County, Yunnan Province, Southwest China. Methods: Tumor tissues from 51 patients with PMe (40 of whom had a history of asbestos exposure) and pleural tissues from 12 non-PMe patients (including diseases such as pulmonary maculopathy and pulmonary tuberculosis) were collected. Three pairs of low-contamination risk primers (SVINT, SVfor2, and SVTA1) were used to detect the gene fragment of SV40 large T antigen (T-Ag) by polymerase chain reaction (PCR). The presence of SV40 T-Ag in PMe tumor tissues and PMe cell lines was detected by Western blotting and immunohistochemical staining with SV40-related antibodies (PAb 101 and PAb 416). Results: PCR, Western blotting, and immunohistochemical staining results showed that the Met5A cell line was positive for SV40 and contained the SV40 T-Ag gene and protein. In contrast, the various PMe cell lines NCI-H28, NCI-H2052, and NCI-H2452 were negative for SV40. PCR was negative for all three sets of low-contamination risk primers in 12 non-PMe tissues and 51 PMe tissues. SV40 T-Ag was not detected in 12 non-PMe tissues or 51 PMe tissues by immunohistochemical staining. Conclusion: Our data suggest that the occurrence of PMe in the crocidolite-contaminated area of Yunnan Province may not be related to SV40 infection and that crocidolite exposure may be the main cause of PMe. The Clinical Trial Registration number: 2020-YXLL20.

Objective: To explore the expression of KAP1 (KRAB-associated protein 1, KAP1) in Malignant pleural mesothelioma (MPM) based on the cancer genome atlas (TCGA) and clinical trials. And elucidate the correlation between the expression of KAP1 and the clinical pathological parameters of patients with MPM and its prognosis. Methods: In April 2022, Based on the second generation KAP1mRNA sequencing data and clinicopathological data of MPM patients downloaded from TCGA database, the correlation between KAP1mRNA expression and clinical parameters was analyzed, and the correlation between KAP1 protein expression and clinicopathological parameters and its prognostic value were analyzed based on Chuxiong data set cohort clinical samples. The expression of KAP1 mRNA in MPM samples and matched normal tumor adjacent tissues was detected by qRT-PCR, and the expression of KAP1 protein in MPM and normal pleural tissues was detected by immunohistochemistry and Westernblotting. To construct a Kaplan-Meier model to explore the effect of KAP1 expression on the prognosis of MPM patients, and to analyze the prognostic factors of MPM patients by Cox regression. Results: qRT-PCR and Western blotting detection showed that the expression levels of KAP1 gene in four different MPM cells (NCI-H28, NCI-H2052, NCI-H2452, and MTSO-211H) were significantly higher than those in normal pleural mesothelial cells Met-5A. qRT-PCR, Western blotting and IHC results demonstrated that the mRNA and protein expression levels of KAP1 in MPM tissues was significantly higher than that in matching normal mesothelial tissues, and the expression level of KAP1 protein was correlated with TP 53 protein expression levels and serum CEA levels ( P <0.05) . The mRNA expression level was significantly correlated with the prognosis, The overall survival time of mesothelioma patients with high KAP1mRNA expression was significantly shorter (HR=3.7, Logrank P <0.001) . Tumor type, age and the mRNA expression were related to the prognosis of MPM patients ( P <0.05) . Multivariate analysis showed that tumor type and KAP1 mRNA expression level were independent prognostic factors of MPM patients ( P <0.05) . Conclusion: In this study, TCGA database and Chuxiong cohort experiment samples were used to collect the relevant information of KAP1 expression in malignant melanoma tissues. It was confirmed that KAP1 is highly expressed in MPM tissues. The mRNA expression level and pathological type are correlated with the prognosis of patients.

Mesothelioma is a type of late-onset cancer that develops in cells covering the outer surface of organs. Although it can affect the peritoneum, heart, or testicles, it mainly targets the lining of the lungs, making pleural mesothelioma (PMe) the most common and widely studied mesothelioma type. PMe is caused by exposure to fibres of asbestos, which when inhaled leads to inflammation and scarring of the pleura. Despite the ban on asbestos by most Western countries, the incidence of PMe is on the rise, also facilitated by a lack of specific symptomatology and diagnostic methods. Therapeutic options are also limited to mainly palliative care, making this disease untreatable. Here we present an overview of biological aspects underlying PMe by listing genetic and molecular mechanisms behind its onset, aggressive nature, and fast-paced progression. To this end, we report on the role of deubiquitinase BRCA1-associated protein-1 (BAP1), a tumour suppressor gene with a widely acknowledged role in the corrupted signalling and metabolism of PMe. This review aims to enhance our understanding of this devastating malignancy and propel efforts for its investigation., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf ofFederation of European Biochemical Societies.)

Pleural mesothelioma (PM) is characterized by rapid growth, local invasion, and limited therapeutic options. The multifunctional oncoprotein Y-box-binding protein-1 (YB-1) is frequently overexpressed in cancer and its inhibition reduces aggressive behavior in multiple tumor types. Here, we investigated the effects of YB-1 on target gene regulation and PM cell behavior. Whereas siRNA-mediated YB-1 knockdown reduced cell motility, YB-1 overexpression resulted in scattering, increased migration, and intravasation in vitro. Furthermore, YB-1 stimulated PM cell spreading in zebrafish. Combined knockdown and inducible overexpression of YB-1 allowed bidirectional control and rescue of cell migration, the pattern of which was closely followed by the mRNA and protein levels of EGFR and the protein level of snail, whereas the mRNA levels of MMP1, EPHA5, and PARK2 showed partial regulation by YB-1. Finally, we identified snail as a critical regulator of YB-1-mediated cell motility in PM. This study provides insights into the mechanism underlying the aggressive nature of PM and highlights the important role of YB-1 in this cancer. In this context, we found that YB-1 closely regulates EGFR and snail, and, moreover, that YB-1-induced cell migration depends on snail., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf ofFederation of European Biochemical Societies.)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited therapeutic options. We evaluated the impact of CDK4/6 inhibition by palbociclib in 28 MPM cell lines including 19 patient-derived ones, using various approaches including RNA-sequencing. Palbociclib strongly and durably inhibited the proliferation of 23 cell lines, indicating a unique sensitivity of MPM to CDK4/6 inhibition. When observed, insensitivity to palbociclib was mostly explained by the lack of active T172-phosphorylated CDK4. This was associated with high p16 INK4A (CDKN2A) levels that accompany RB1 defects or inactivation, or (unexpectedly) CCNE1 overexpression in the presence of wild-type RB1. Prolonged palbociclib treatment irreversibly inhibited proliferation despite re-induction of cell cycle genes upon drug washout. A senescence-associated secretory phenotype including various potentially immunogenic components was irreversibly induced. Phosphorylated CDK4 was detected in 80% of 47 MPMs indicating their sensitivity to CDK4/6 inhibitors. Its absence in some highly proliferative MPMs was linked to very high p16 (CDKN2A) expression, which was also observed in public datasets in tumours from short-survival patients. Our study supports the evaluation of CDK4/6 inhibitors for MPM treatment, in monotherapy or combination therapy., (© 2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The occurrence of malignant mesothelioma is related to exposure of asbestos. And many researchers have conducted in-depth analysis of the molecular changes of mesothelioma, showed that its molecular characteristics were chromosome changes, including chromosome rearrangement, gene mutation and gene deletion. Recent studies have strengthened our understanding of molecular characterization of mesothelioma, such as targeted mutations of tumor suppressor genes, differential gene expression, changes of miRNA and signal pathways. It is of great significance for the early diagnosis, clinical treatment and prognosis of malignant mesothelioma to explore the pathogenesis and development of malignant mesothelioma. This article reviews the research progress on the pathogenesis and carcinogenesis-related molecules of malignant mesothelioma.

9p21 deletions involving MTAP/CDKN2A genes are detected in diffuse pleural mesotheliomas (DPM) but are absent in benign mesothelial proliferations. Loss of MTAP expression by immunohistochemistry (IHC) is well accepted as a surrogate for 9p21 deletion to support a diagnosis of DPM. Accurate interpretation can be critical in the diagnosis of DPM, but variations in antibody performance may impact interpretation. The objectives of this study were to compare the performance of MTAP monoclonal antibodies (mAbs) EPR6893 and 1813 and to compare MTAP expression by IHC with 9p21 copy number status in DPM. Cytoplasmic expression of MTAP IHC with mAbs EPR6893 (ab126770; Abcam) and 1813 (NBP2-75730, Novus Biologicals) was evaluated in 56 DPM (47 epithelioid, 7 biphasic, and 2 sarcomatoid) profiled by targeted next-generation sequencing. 9p21 Copy number status was assessed by Fraction and Allele-Specific Copy Number Estimates from Tumor Sequencing (FACETS) analysis and also by CDKN2A fluorescence in situ hybridization in discrepant cases when material was available. MTAP mAb 1813 showed stronger immunoreactivity, more specific staining, and no equivocal interpretations compared to mAb EPR6893 which showed equivocal staining in 19 (34%) of cases due to weak or heterogenous immunoreactivity, lack of definitive internal positive control, and/or nonspecific background staining. MTAP expression with mAb 1813 showed near perfect agreement with 9p21 copy number by combined FACETS/fluorescence in situ hybridization calls (κ = 0.85; 95% CI, 0.71-0.99; P < .001). MTAP IHC with mAb 1813 was 96% sensitive, 86% specific, and 93% accurate for 9p21 homozygous deletion. The findings of this study suggest that interpretation of MTAP IHC is improved with mAb 1813 because mAb EPR6893 was often limited by equivocal interpretations. We show that MTAP IHC and molecular assays are complementary in detecting 9p21 homozygous deletion. MTAP IHC may be particularly useful for low tumor purity samples and in low-resource settings., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Dry gene powder is a novel non-viral gene-delivery system, which is inhalable with high gene expression. Previously, we showed that the transfection of p16 INK4a or TP53 by dry gene powder resulted in growth inhibitions of lung cancer and malignant pleural mesothelioma (MPM) in vitro and in vivo. Here, we report that dry gene powder containing p53- expression-plasmid DNA enhanced the therapeutic effects of cisplatin (CDDP) against MPM even in the presence of endogenous p53. Furthermore, our results indicated that the safe transfection with a higher plasmid DNA (pDNA) concentration suppressed MPM growth independently of chemotherapeutic agents. To develop a new therapeutic alternative for MPM patients without safety concerns over "vector doses", our in vitro data provide basic understandings for dry gene powder., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background/aim: The prognosis of patients with malignant pleural mesothelioma (MPM) remains poor due to lack of effective therapeutic targets. DNA damage caused by long-time exposure to asbestos fibers has been associated with the development of MPM, with mutations at genes encoding DNA damage repair (DDR)-related molecules frequently expressed in patients with MPM. The present study was designed to identify novel therapeutic targets in MPM using large public databases, such as The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression project (GTEx) focused on DDR pathways., Materials and Methods: The correlations between mRNA expression levels of DDR-related genes and overall survival (OS) were analyzed in mesothelioma patients in TCGA mesothelioma (TCGA-MESO) datasets. The anti-tumor effects of small interfering RNAs (siRNA) against DDR-related genes associated with OS were subsequently tested in MPM cell lines., Results: High levels of mRNA encoding DNA polymerase delta 1, catalytic subunit (POLD1) were significantly associated with reduced OS in patients with MPM (p<0.001, Log-rank test). In addition, siRNA targeting POLD1 (siPOLD1) caused cell cycle arrest at the G 1 /S checkpoint and induced apoptosis involving accumulation of DNA damage in MPM cell lines., Conclusion: POLD1 plays essential roles in overcoming DNA damage and cell cycle progression at the G 1 /S checkpoint in MPM cells. These findings suggest that POLD1 may be a novel therapeutic target in MPM., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm of the pleural tissue that lines the lungs and is mainly associated with long latency from asbestos exposure. This tumor has no effective therapeutic opportunities nowadays and has a very low five-year survival rate. In this sense, identifying molecular events that trigger the development and progression of this tumor is highly important to establish new and potentially effective treatments. We conducted a meta-analysis of genome-wide expression studies publicly available at the Gene Expression Omnibus (GEO) and ArrayExpress databases. The differentially expressed genes (DEGs) were identified, and we performed functional enrichment analysis and protein-protein interaction networks (PPINs) to gain insight into the biological mechanisms underlying these genes. Additionally, we constructed survival prediction models for selected DEGs and predicted the minimum drug inhibition concentration of anticancer drugs for MPM. In total, 115 MPM tumor transcriptomes and 26 pleural tissue controls were analyzed. We identified 1046 upregulated DEGs in the MPM samples. Cellular signaling categories in tumor samples were associated with the TNF, PI3K-Akt, and AMPK pathways. The inflammatory response, regulation of cell migration, and regulation of angiogenesis were overrepresented biological processes. Expression of SOX17 and TACC1 were associated with reduced survival rates. This meta-analysis identified a list of DEGs in MPM tumors, cancer-related signaling pathways, and biological processes that were overrepresented in MPM samples. Some therapeutic targets to treat MPM are suggested, and the prognostic potential of key genes is shown., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The pleural lining of the thorax regulates local immunity, inflammation and repair. A variety of conditions, both benign and malignant, including pleural mesothelioma, can affect this tissue. A lack of knowledge concerning the mesothelial and stromal cells comprising the pleura has hampered the development of targeted therapies. Here, we present the first comprehensive single-cell transcriptomic atlas of the human parietal pleura and demonstrate its utility in elucidating pleural biology. We confirm the presence of known universal fibroblasts and describe novel, potentially pleural-specific, fibroblast subtypes. We also present transcriptomic characterisation of multiple in vitro models of benign and malignant mesothelial cells, and characterise these through comparison with in vivo transcriptomic data. While bulk pleural transcriptomes have been reported previously, this is the first study to provide resolution at the single-cell level. We expect our pleural cell atlas will prove invaluable to those studying pleural biology and disease. It has already enabled us to shed light on the transdifferentiation of mesothelial cells, allowing us to develop a simple method for prolonging mesothelial cell differentiation in vitro ., Competing Interests: Conflicts of interest: In addition to the funding acknowledged in the support statement, the following conflicts are declared by the authors. J. Obacz reports grants from Victor Dahdaleh Charitable Foundation. A.S. Coonar reports grants from Innovate UK, consultancy for Viderigen, honoraria for lectures from AstraZeneca, book royalties from Springer Nature, payment for expert testimony from Medicolegal reports, leadership or fiduciary roles for Society for Cardiothoracic Surgery of GB and Ireland, and is Chair of the Thoracic Surgery Committee, NHS, National Clinical Lead for NHS England and a Governor of Royal Papworth Hospital. A. Peryt reports lecture honoraria from AstraZeneca, and travel support from Albyn Medical. N. Kaminski is a scientific founder at Thyron, served as a consultant to Biogen Idec, Boehringer Ingelheim, Third Rock, Pliant, Samumed, NuMedii, Theravance, LifeMax, Three Lake Partners, Optikira, AstraZeneca, RohBar, Veracyte, Augmanity, CSL Behring, Galapagos, Gilead, Chiesi, Arrowhead, Sofinnova and Thyron over the last 3 years, reports Equity in Pliant and Thyron, and grants from Veracyte, Boehringer Ingelheim, BMS and Three Lakes Foundation, and non-financial support from MiRagen and Astra Zeneca; N. Kaminski also has the following patents licensed to biotech: New therapies for IPF, New Therapies for ARDS and New Biomarkers in IPF. M.J. Garnett reports consultancy fees from and equity in Mosaic Therapeutics, and has a patent pending for describing suspension organoid cultures. R.C. Rintoul is chief investigator of Mesobank UK and is part funded by Asthma+Lung UK. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Purpose: Pleural mesothelioma (PM) is an aggressive tumor still considered incurable, in part due to the lack of predictive biomarkers. Little is known about the clinical implications of molecular alterations in resectable PM tissues and blood. Here, we characterized genetic alterations to identify prognostic and predictive biomarkers in patients with resected PM., Experimental Design: Targeted next-generation sequencing was performed in retrospective pleural tumor tissue and paired plasma samples from stage IB-IIIB resected PM. Association between prognosis and presence of specific mutations was validated in silico., Results: Thirty PM tissues and paired blood samples from 12 patients were analyzed. High tissue tumor mutational burden (TMB) (>10 mutations/Mb), tissue median minor allele frequency (MAF) (>9 mutations/Mb), and blood TMB (>6 mutations/Mb), tissue KMT2C, PBRM1, PKHD1,EPHB1 and blood LIFR mutations correlated with longer disease-free survival and/or overall survival. High concordance (>80%) between tissue and blood was found for some mutations., Conclusions: Tissue TMB and MAF, blood TMB, and specific mutations correlated with outcomes in patients with resected PM and should be further studied to validate their role as prognostic biomarkers and potentially predictive factors for combinations with immune-checkpoint inhibitors. This suggest that molecular profiling could identify longer survivors in patients with resected PM., Competing Interests: Declaration of Competing Interest Umberto Malapelle has received personal fees (as consultant and/or speaker bureau) from Boehringer Ingelheim, Roche, MSD, Amgen, Thermo Fisher Scientifics, Eli Lilly, Diaceutics, GSK, Merck, AstraZeneca, Janssen, Diatech, Novartis and Hedera unrelated to the current work. Pasquale Pisapia has received personal fees as speaker bureau from Novartis, for work performed outside of the current study. Giancarlo Troncone reports personal fees (as speaker bureau or advisor) from Roche, MSD, Pfizer, Boehringer Ingelheim, Eli Lilly, BMS, GSK, Menarini, AstraZeneca, Amgen, and Bayer unrelated to the current work. Alessandro Russo reports advisory board role/consultancy from AstraZeneca, MSD, Novartis, Pfizer, BMS, Roche, and Amgen unrelated to the current work. Andres F. Cardona discloses financial research support from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol‐Myers Squibb, Foundation Medicine, Roche Diagnostics, Thermo Fisher, Broad Institute, BioNTech, Amgen, Flatiron Health, Teva Pharma, Rochem Biocare, Bayer, INQBox and The Foundation for Clinical and Applied Cancer Research – FICMAC; advisor role to EISAI, Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol‐Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research – FICMAC outside the submitted work. Marzia Del Re has received research grants from Astellas and AstraZeneca, consulting fees from Janssen, AstraZeneca, Astellas, discloses speaker bureau role for AstraZeneca, Astellas, Janssen, Novartis, Roche, Daiicho Sankyo, Takeda, advisory board role for Novartis, Roche, and Amgen outside the submitted work. Ashutosh Sachdeva reports consulting fees from AMBU and MERIT, advisory board role for AMBU not related to the submitted work. Fred R. Hirsch reports advisory boards consultancy for Bristol‐Myers Squibb, AstraZeneca/Daiichi, Sanofi/Regeneron, Novartis, Amgen, OncoCyte, Genentech, and Nectin Therapeutics unrelated to the current work. Christian Rolfo is a speaker for Merck Sharp and Dohme, AstraZeneca, COR2ED, Daiichi Sankyo, Physicians Education Resource, and Roche (CH); has research collaborations (nonfinancial support) with Guardant Health; advisory board activity: Archer, Inivata, Bayer U.C. LLC, Boston pharmaceutical, CEA, MD Serono, General Dynamics, MedStar, Novartis, Sanofi Genzyme‐Regeneron. Provides expert testimony to Intellisphere, scientific board for Imagene, and is a coordinating PI for MD Serono Global PI LUNG itrapid@ 024 trial. Research grant from LCRF‐Pfizer unrelated to the current work. The other authors declare no competing interest., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Lymphocyte-activation gene 3 (LAG3) is an immune checkpoint receptor; novel LAG3 immune checkpoint inhibitors (ICIs) exhibit therapeutic activity in melanoma. The role of LAG3and ICIs of LAG3 are unknown in malignant pleural mesothelioma (MPM). This study aimed to uncover the prognostic landscape of LAG3 in multiple cancers and investigate the potential of using LAG3 as an ICIs target in patients with MPM., Methods: We used The Cancer Genome Atlas (TCGA) cohort for assessing mRNA expression and our cohort for immunohistochemical expression. TCGA cohort were analyzed using the Wilcoxon rank-sum test to compare mRNA expression between normal and tumor tissues in multiple cancers. We used 86 MPM cases from TCGA and 38 MPM cases from our cohort to analyze the expression of LAG3 in tumor-infiltrating lymphocytes. The mean LAG3 mRNA expression was set as the cut-off and samples were classified as positive/negative for immunohistochemical expression. Overall survival (OS) of patients with MPM was determined using the Kaplan-Meier method based on LAG3 mRNA and immunohistochemical expression. OS analysis was performed using the multivariate Cox proportional hazards model. The correlation of LAG3 expression and mRNA expression of tumor immune infiltration cells (TIICs) gene markers were estimated using Spearman correlation. To identify factors affecting the correlation of LAG3 mRNA expression, a multivariate linear regression model was performed., Results: LAG3 mRNA was associated with prognosis in multiple cancers. Elevated LAG3 mRNA expression was correlated with a better prognosis in MPM. LAG3 expression was detected immunohistochemically in the membrane of infiltrating lymphocytes in MPM. LAG3 immunohistochemical expression was correlated with a better prognosis in MPM. The multivariate Cox proportional hazards model revealed that elevated LAG3 immunohistochemical expression indicated a better prognosis. In addition, LAG3 mRNA expression was correlated with the expression of various gene markers of TIICs, the most relevant to programmed cell death 1 (PD-1) with the multivariate linear regression model in MPM., Conclusions: LAG3 expression was correlated with prognosis in multiple cancers, particularly MPM; LAG3 is an independent prognostic biomarker of MPM. LAG3 regulates cancer immunity and is a potential target for ICIs therapy. PD-1 and LAG3 inhibitors may contribute to a better prognosis in MPM., Trial Registration: This study was registered with UMIN000049240 (registration day: August 19, 2022) and approved by the Institutional Review Board (approval date: August 22, 2022; approval number: 2022-0048) at Tokyo Women's Medical University., (© 2023. The Author(s).)

Purpose of Review: In this article, we provide a comprehensive analysis of recent progress in the genetic characterisation of pleural mesothelioma, and the translation of these findings to clinical practice., Recent Findings: Advancements in sequencing technology have allowed the identification of driver mutations and improved our understanding of how these mutations may shape the mesothelioma tumour microenvironment. However, the identification of frequently mutated regions including CDKN2A, BAP1 and NF2 have, to date, not yet yielded targeted therapy options that outperform standard chemo- and immunotherapies. Similarly, the association between mutational profile and the immune microenvironment or immunotherapy response is not well characterised. Further research into the link between tumour mutational profile and response to therapy is critical for identifying targetable vulnerabilities and stratifying patients for therapy., (© 2023. The Author(s).)

Background: Overlapping morphological features of mesothelial cells have been rendered it difficult to distinguish between reactive and malignant conditions. The development of methods based on detecting genomic abnormalities using immunohistochemistry and fluorescence in situ hybridization have contributed markedly to solving this problem. It is important to identify bland mesothelioma cells on cytological screening, perform efficient genomic-based testing, and diagnose mesothelioma, because the first clinical manifestation of pleural mesothelioma is pleural effusion, which is the first sample available for pathological diagnosis. However, certain diagnostic aspects remain challenging even for experts., Case Presentation: This report describes a case of a 72-year-old man with a history of asbestos exposure who presented with pleural effusion as the first symptom and was eventually diagnosed as mesothelioma. Mesothelioma was suspected owing to prominent cell-in-cell engulfment in mesothelial cells on the first cytological sample, and the diagnosis of mesothelioma in situ was confirmed by histology. Unexpectedly, sarcomatoid morphology of mesothelioma was found in the second pathology samples 9 months after the first pathological examination. Both the mesothelioma in situ and invasive lesion showed immunohistochemical loss of methylthioadenosine phosphorylase (MTAP) and homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) on fluorescence in situ hybridization. The patient received medication therapy but died of disease progression 12 months after the diagnosis of the sarcomatoid morphology of mesothelioma., Conclusion: Our case suggests that cell-in-cell engulfment can be conspicuous in early-stage mesothelioma with inconspicuous nuclear atypia and few multinucleated cells. In addition, the presence of MTAP loss and CDKN2A homozygous deletion are suspected to be involved in early formation to invasive lesions and/or sarcomatoid morphology. We believe that it is important to consider genetic abnormalities when deciding on individual patient management. Furthermore, cases of mesothelioma, even those of an in situ lesion, with MTAP loss and/or CDKN2A deletion should be carefully followed up or subjected to early treatment., (© 2023. The Author(s).)

Pleural mesothelioma (PM) is characterized by poor prognosis and limited therapeutic options. Y-box-binding protein 1 (YB-1) was shown to drive growth and migration of PM cells. Here, we evaluated the effect of genetic and pharmacological targeting of YB-1 on PM growth and response to cisplatin and radiation treatment. YB-1 knockdown via siRNA resulted in reduced PM cell growth, which significantly correlated with wt BAP1 and mutant NF2 and P53 status. Entinostat inhibited YB-1 deacetylation and its efficacy correlated with YB-1 knockdown-induced growth inhibition in 20 PM cell lines. Tumor growth inhibition by siRNA as well as entinostat was confirmed in mouse xenotransplant models. Furthermore, both YBX1-targeting siRNA and entinostat enhanced sensitivity to cisplatin and radiation. In particular, entinostat showed strong synergistic interactions with cisplatin which was linked to significantly increased cellular platinum uptake in all investigated cell models. Importantly, in a mouse model, the combination of cisplatin and entinostat also resulted in stronger growth inhibition than each treatment alone. Our study highlights YB-1 as an attractive target in PM and demonstrates that targeting YB-1 via entinostat is a promising approach to enhance cisplatin and radiation sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To investigate the inhibitory effect of microRNA-106b in the process of migration and invasion of human malignant pleural mesothelioma cell NCI-H2452. Methods: In April 2017, the expression level of miRNA-106b in malignant pleural mesothelioma cells (NCI-H2452, MSTO-211H, NCI-H2052) and normal mesothelial cells MeT-5A was detected and analyzed. Using NCI-H2452 cells as a model, the NCI-H2452 cell model with miRNA-106b overexpression was established by transfecting miRNA-106b mimics. The expression level of miRNA-106b in the cells was detected by real-time fluorescent quantitative PCR. The effect of miRNA-106b on the migration and invasion ability of NCI-H2452 cells was analyzed. The gene expression data of malignant mesothelioma and the downstream target gene data of miRNA-106b in public databases were analyzed to screen the downstream target genes of miRNA-106b in mesothelioma cells that affect cell migration and invasion ability, and to verify the expression of this gene in NCI-H2452 cells with miRNA-106b overexpression. Results: The expression of miRNA-106b in three MPM cells was decreased compared with MeT-5A cells ( P <0.001) . The expression level of miRNA-106b was significantly increased after transfection of miRNA-106b mimics ( P <0.001) . The scratch migration levels of the experimental group were 28.45%±4.37%, 38.12%±4.82% and 50.06%±8.92% at 24h, 31h and 48h, respectively. Compared with the control group, the migration level decreased by 37.48%±2.65%, 49.21%±3.45% and 68.14%±3.81% ( P <0.01) . The number of cell migration and invasion decreased in the experimental group compared with the control group ( P <0.001) . Public databases were used to screen and analyze the possibility that TCF21 gene, as a downstream target gene, could affect the migration and invasion ability of MPM cells. The expression level of TCF21 gene was increased after transfection of miRNA-106b mimics in NCI-H2452 cells ( P =0.009) . Conclusion: MiRNA-106b can inhibit the migration and invasion of NCI-H2452 cells and increase the expression of TCF21 gene.

Objectives: Mesothelioma is a lethal disease that arises from the serosal lining of organ cavities. Several recurrent alterations have been observed in pleural and peritoneal -mesotheliomas, including in BAP1, NF2, and CDKN2A. Although specific histopathologic parameters have been correlated with prognosis, it is not as well known whether genetic alterations correlate with histologic findings., Methods: We reviewed 131 mesotheliomas that had undergone next-generation sequencing (NGS) at our institutions after pathologic diagnosis. There were 109 epithelioid mesotheliomas, 18 biphasic mesotheliomas, and 4 sarcomatoid mesotheliomas. All our biphasic and sarcomatoid cases arose in the pleura. Of the epithelioid mesotheliomas, 73 were from the pleura and 36 were from the peritoneum. On average, patients were 66 years of age (range, 26-90 years) and predominantly male (92 men, 39 women)., Results: The most common alterations identified were in BAP1, CDKN2A, NF2, and TP53. Twelve mesotheliomas did not show a pathogenic alteration on NGS. For epithelioid mesotheliomas in the pleura, the presence of an alteration in BAP1 correlated with low nuclear grade (P = .04), but no correlation was found in the peritoneum (P = .62). Similarly, there was no correlation between the amount of solid architecture in epithelioid mesotheliomas and any alterations in the pleura (P = .55) or peritoneum (P = .13). For biphasic mesotheliomas, cases with either no alteration detected or with an alteration in BAP1 were more likely to be epithelioid predominant (>50% of the tumor, P = .0001), and biphasic mesotheliomas with other alterations detected and no alteration in BAP1 were more likely to be sarcomatoid predominant (>50% of the tumor, P = .0001)., Conclusions: This study demonstrates a significant association between morphologic features associated with a better prognosis and an alteration in BAP1., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We previously demonstrated that cullin 4B (CUL4B) upregulation was associated with worse outcomes of pleural mesothelioma (PM) patients, while the overexpression of its paralog CUL4A was not associated with clinical outcomes. Here, we aimed to identify the distinct roles of CUL4B and CUL4A in PM using an siRNA approach in PM cell lines (ACC Meso-1 and Mero82) and primary culture. The knockdown of CUL4B and CUL4A resulted in significantly reduced colony formation, increased cell death, and delayed cell proliferation. Furthermore, similar to the effect of CUL4A knockdown, downregulation of CUL4B led to reduced expression of Hippo pathway genes including YAP1, CTGF, and survivin. Interestingly, CUL4B and not CUL4A knockdown reduced TGF-β1 and MMP2 expression, suggesting a unique association of CUL4B with this pathway. However, the treatment of PM cells with exogenous TGF-β1 following CUL4B knockdown did not rescue PM cell growth. We further analyzed ACC Meso-1 xenograft tumor tissues treated with the cullin inhibitor, pevonedistat, which targets protein neddylation, and observed the downregulation of human TGF-β1 and MMP2. In summary, our data suggest that CUL4B overexpression is important for tumor cell growth and survival and may drive PM aggressiveness via the regulation of TGF-β1 expression and, furthermore, reveal a new mechanism of action of pevonedistat.

Pleural mesothelioma (PM) is an aggressive malignancy that develops in a unique tumor microenvironment (TME). However, cell models for studying the TME in PM are still limited. Here, we have generated and characterized novel human telomerase reverse transcriptase (hTERT)-transduced mesothelial cell and mesothelioma-associated fibroblast (Meso-CAF) models and investigated their impact on PM cell growth. Pleural mesothelial cells and Meso-CAFs were isolated from tissue of pneumothorax and PM patients, respectively. Stable expression of hTERT was induced by retroviral transduction. Primary and hTERT-transduced cells were compared with respect to doubling times, hTERT expression and activity levels, telomere lengths, proteomes, and the impact of conditioned media (CM) on PM cell growth. All transduced derivatives exhibited elevated hTERT expression and activity, and increased mean telomere lengths. Cell morphology remained unchanged, and the proteomes were similar to the corresponding primary cells. Of note, the CM of primary and hTERT-transduced Meso-CAFs stimulated PM cell growth to the same extent, while CM derived from mesothelial cells had no stimulating effect, irrespective of hTERT expression. In conclusion, all new hTERT-transduced cell models closely resemble their primary counterparts and, hence, represent valuable tools to investigate cellular interactions within the TME of PM.

Background: Pleural mesothelioma (PM) is a relatively rare malignancy with limited treatment options and dismal prognosis. We have previously found elevated FGF18 expression in PM tissue specimens compared with normal mesothelium. The objective of the current study was to further explore the role of FGF18 in PM and evaluate its suitability as a circulating biomarker., Methods: FGF18 mRNA expression was analyzed by real-time PCR in cell lines and in silico in datasets from the Cancer Genome Atlas (TCGA). Cell lines overexpressing FGF18 were generated by retroviral transduction and cell behavior was investigated by clonogenic growth and transwell assays. Plasma was collected from 40 PM patients, six patients with pleural fibrosis, and 40 healthy controls. Circulating FGF18 was measured by ELISA and correlated to clinicopathological parameters., Results: FGF18 showed high mRNA expression in PM and PM-derived cell lines. PM patients with high FGF18 mRNA expression showed a trend toward longer overall survival (OS) in the TCGA dataset. In PM cells with low endogenous FGF18 expression, forced overexpression of FGF18 resulted in reduced growth but increased migration. Surprisingly, despite the high FGF18 mRNA levels observed in PM, circulating FGF18 protein was significantly lower in PM patients and patients with pleural fibrosis than in healthy controls. No significant association of circulating FGF18 with OS or other disease parameters of PM patients was observed., Conclusions: FGF18 is not a prognostic biomarker in PM. Its role in PM tumor biology and the clinical significance of decreased plasma FGF18 in PM patients warrant further investigation., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Mesothelioma is the primary tumor of the mesothelial cell membrane. The most important etiology is asbestos exposure. The development of malignant mesothelioma in very few of the population exposed to asbestos and its frequent occurrence in some families may be significant in terms of genetic predisposition. Again, the presence of relatives with mesothelioma who did not have asbestos contact strengthens this argument. This disease, which has limited treatment options and has a poor prognosis, revealing a genetic predisposition, if any, may prolong survival with early diagnosis and effective treatment., Methods: Based on the genetic predisposition idea, we diagnosed and followed a total of ten individuals of relatives with mesothelioma. DNA was isolated from peripheral blood and whole genome sequencing analysis was done. Common gene mutations in ten individuals were filtered using bioinformatics. After this filter, from the remaining variants, very rare in the population and damaging mutations are selected., Results: Eight thousand six hundred and twenty-two common variants have been identified in ten individuals with this analysis. In total, 120 variants were found on 37 genes in 15 chromosomes. These genes are PIK3R4, SLC25A5, ITGB6, PLK2, RAD17, HLA-B, HLA-DRB1, HLA-DQB1, GRM, IL20RA, MAP3K7, RIPK2, and MUC16., Conclusion: Our finding, PIK3R4 gene, is directly associated with mesothelioma development. Twelve genes, which are associated with cancer, were detected in literature. Additional studies, which scan first-degree relatives of individual, are needed to find the specific gene region., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Malignant Pleural Mesothelioma (MPM) is a dreadful disease escaping the classical genetic model of cancer evolution and characterized by wide heterogeneity and transcriptional plasticity. Clinical evolution of MPM is marked by a progressive transdifferentiation that converts well differentiated epithelioid (E) cells into undifferentiated and pleomorphic sarcomatoid (S) phenotypes. Catching the way this transition takes place is necessary to understand how MPM develops and progresses and it is mandatory to improve patients' management and life expectancy. Bulk transcriptomic approaches, while providing a significant overview, failed to resolve the timing of this evolution and to identify the hierarchy of molecular events through which this transition takes place., Methods: We applied a spatially resolved, high-dimensional transcriptomic approach to study MPM morphological evolution. 139 regions across 8 biphasic MPMs (B-MPMs) were profiled using the GeoMx™Digital Spatial Profiler to reconstruct the positional context of transcriptional activities and the spatial topology of MPM cells interactions. Validation was conducted on an independent large cohort of 84 MPMs by targeted digital barcoding analysis., Results: Our results demonstrated the existence of a complex circular ecosystem in which, within a strong asbestos-driven inflammatory environment, MPM and immune cells affect each other to support S-transdifferentiation. We also showed that TGFB1 polarized M2-Tumor Associated Macrophages foster immune evasion and that TGFB1 expression correlates with reduced survival probability., Conclusions: Besides providing crucial insights into the multidimensional interactions governing MPM clinical evolution, these results open new perspectives to improve the use of immunotherapy in this disease., (© 2023. The Author(s).)

Malignant pleural mesothelioma (MPM) is a rare but invasive cancer, which mainly arises from mesothelial tissues of pleura, peritoneum and pericardium. Despite significant advances in treatments, the prognosis of MPM patients remains poor, and the 5-year survival rate is less than 10%. Therefore, it is urgent to explore novel therapeutic targets for the treatment of MPM. Growing evidence has indicated that long non-coding RNAs (lncRNAs) potentially could be promising therapeutic targets for numerous cancers. In this regard, lncRNAs might also potentially therapeutic targets for MPM. Recent advances have been made to investigate the molecular basis of MPM. This review first provides a comprehensive overview of roles of lncRNAs in MPM and then discusses the relationship between molecular basis of MPM and MPM-related lncRNAs to implement them as promising therapeutic targets for MPM., Competing Interests: Declaration of Competing Interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology., Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799., (©2023 The Authors; Published by the American Association for Cancer Research.)

Objectives: Malignant pleural mesothelioma (MPM) is an aggressive cancer which at large is not amenable to curative surgery. Despite the recent approval of immune checkpoint inhibitor therapy, the response rates and survival following systemic therapy is still limited. Sacituzumab govitecan is an antibody-drug conjugate targeting the topoisomerase I inhibitor SN38 to trophoblast cell-surface antigen 2 (TROP-2)-positive cells. Here we have explored the therapeutic potential of sacituzumab govitecan in MPM models., Materials and Methods: TROP2 expression was analyzed in a panel of two well established and 15 pleural effusion derived novel lines by RT-QPCR and immunoblotting, TROP2 membrane-localization was studied by flow cytometry and immunohistochemistry. Cultured mesothelial cells and pneumothorax pleura served as controls. The sensitivity of MPM cell lines to irinotecan and SN38 was studied using cell viability, cell cycle, apoptosis and DNA damage assays. Drug sensitivity of cell lines was correlated with RNA expression of DNA repair genes. Drug sensitivity was defined as an IC50 below 5 nM in the cell viability assay., Results: TROP2 expression was detected at RNA and protein level in 6 of the 17 MPM cell lines, but not in in cultured mesothelial control cells or in the mesothelial layer of the pleura. TROP2 was detectable on the cell membrane in 5 MPM lines and was present in the nucleus in 6 cell models. Ten of 17 MPM cell lines showed sensitivity to SN38 treatment, among those 4 expressed TROP2. High AURKA RNA expression and high proliferation rate correlated with sensitivity to SN38-induced cell death, DNA damage response, cell cycle arrest and cell death. Sacituzumab govitecan treatment effectively induced cell cycle arrest and cell death in TROP2-positive MPM cells., Conclusion: TROP2 expression and sensitivity to SN38 in MPM cell lines support biomarker-selected clinical exploration of sacituzumab govitecan in patients with MPM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM., (© 2023. The Author(s).)

Objectives: Malignant pleural mesothelioma (MPM) is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options. For MPM patients, the effectiveness of immunotherapy may be influenced by damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy., Methods: The RNA-seq of 397 patients (263 patients with clinical data, 57.2% male, 73.0% over 60 yrs.) were gathered from eight public datasets as a training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis. Three validation cohorts of patients or murine were established from TCGA and GEO databases. Comparisons were made across each subtype's immune status, gene mutations, survival prognosis, and predicted response to therapy., Results: Based on the DAMPs gene expression, MPMs were categorized into two subtypes: the nuclear DAMPs subtype, which is classified by the upregulation of immune-suppressed pathways, and the inflammatory DAMPs subtype, which is distinguished by the enrichment of proinflammatory cytokine signaling. The inflammatory DAMPs subgroup had a better prognosis, while the nuclear DAMPs subgroup exhibited a worse outcome. In validation cohorts, the subtyping system was effectively verified. We further identified the genetic differences between the two DAMPs subtypes. It was projected that the inflammatory DAMPs subtype will respond to immunotherapy more favorably, suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy., Conclusion: We constructed a subtyping model based on ICD-associated DAMPs in MPM, which might serve as a signature to gauge the outcomes of immune checkpoint blockades. Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Wan, Bai and Wang.)

Objective: To investigate the expression of CD24 gene in human malignant pleural mesothelioma (MPM) cells and tissues, and evaluate its relationship with clinicopathological characteristics and clinical prognosis of MPM patients. Methods: In February 2021, UALCAN database was used to analyze the correlation between CD24 gene expression and clinicopathological characteristics in 87 cases of MPM patients. The TIMER 2.0 platform was used to explore the relationship between the expression of CD24 in MPM and tumor immune infiltrating cells. cBioportal online tool was used to analyze the correlation between CD24 and MPM tumor marker gene expression. RT-qPCR was used to analyze the expressions of CD24 gene in human normal pleural mesothelial cell lines LP9 and MPM cell lines NCI-H28 (epithelial type), NCI-H2052 (sarcoma type), and NCI-H2452 (biphasic mixed type). RT-qPCR was performed to detect the expressions of CD24 gene in 18 cases of MPM tissues and matched normal pleural tissues. The expression difference of CD24 protein in normal mesothelial tissue and MPM tissue was analyzed by immunohistochemistry. A Kaplan-Meier model was constructed to explore the influence of CD24 gene expression on the prognosis of MPM patients, and Cox regression analysis of prognostic factors in MPM patients was performed. Results: The CD24 gene expression without TP53 mutation MPM patients was significantly higher than that of patients in TP53 mutation ( P <0.05). The expression of CD24 gene in MPM was positively correlated with B cells ( r (s)=0.37, P <0.001). The expression of CD24 gene had a positive correlation with the expressions of thrombospondin 2 (THBS2) ( r (s)=0.26, P <0.05), and had a negative correlation with the expression of epidermal growth factor containing fibulin like extracellular matrix protein 1 (EFEMP1), mesothelin (MSLN) and calbindin 2 (CALB2) ( r (s)=-0.31, -0.52, -0.43, P <0.05). RT-qPCR showed that the expression level of CD24 gene in MPM cells (NCI-H28, NCI-H2052 and NCI-H2452) was significantly higher than that in normal pleural mesothelial LP9 cells. The expression level of CD24 gene in MPM tissues was significantly higher than that in matched normal pleural tissues ( P <0.05). Immunohistochemistry showed that the expressions of CD24 protein in epithelial and sarcoma MPM tissues were higher than those of matched normal pleural tissues. Compared with low expression of CD24 gene, MPM patients with high expression of CD24 gene had lower overall survival ( HR =2.100, 95% CI : 1.336-3.424, P <0.05) and disease-free survival ( HR =1.800, 95% CI : 1.026-2.625, P <0.05). Cox multivariate analysis showed that compared with the biphasic mixed type, the epithelial type was a protective factor for the prognosis of MPM patients ( HR =0.321, 95% CI : 0.172-0.623, P <0.001). Compared with low expression of CD24 gene, high expression of CD24 gene was an independent risk factor for the prognosis of MPM patients ( HR =2.412, 95% CI : 1.291-4.492, P =0.006) . Conclusion: CD24 gene and protein are highly expressed in MPM tissues, and the high expression of CD24 gene suggests poor prognosis in MPM patients.

Context.—: Homozygous deletion (HD) of CDKN2A is one of the most frequent genetic abnormalities in pleural mesotheliomas. HD of CDKN2A by fluorescence in situ hybridization (FISH) is a reliable marker of malignancy in mesothelial proliferations; however, evaluation of CDKN2A deletion requires FISH. The 9p21 locus includes both CDKN2A and MTAP (methylthioadenosine phosphorylase); the latter is frequently codeleted with CDKN2A., Objective.—: To examine the question of whether immunohistochemistry for MTAP and p16, the protein product of CDKN2A, can serve as a surrogate for CDKN2A HD by FISH., Design.—: A random selection of 125 pleural mesothelioma cases was divided into 3 groups for evaluation of p16 and MTAP expression compared with FISH for CDKN2A deletion: 53 with HD, 39 with heterozygous deletion, and 33 without deletion., Results.—: By itself, loss of p16 nuclear expression (<1% staining) showed a high sensitivity (96%) but low specificity (43%) for CDKN2A HD by FISH. MTAP cytoplasmic expression loss (≤30% staining) showed a 97% specificity and 69% sensitivity. The combination of p16 nuclear (<1% staining) and MTAP cytoplasmic (≤30% staining) loss demonstrated both high specificity (96%) and high sensitivity (86%). Patients with retained p16 expression (≥1%) had the best prognosis, whereas a p16 (<1%)/MTAP loss combination was associated with a dismal prognosis., Conclusions.—: MTAP immunohistochemical staining is a valid surrogate marker for CDKN2A HD by FISH; however, to obtain the same accuracy as the FISH assay, a combination of nuclear p16 and cytoplasmic MTAP staining is recommended. These findings correlate with prognosis.

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., (© 2022 UICC.)

Pleural mesothelioma (PM) is a cancer where epithelioid, biphasic and sarcomatoid histotypes are observed. Sarcomatoid PM is characterized by mesenchymal features. Multi-omics have been used to characterize the epithelial-to-mesenchymal (EMT) phenotype at the molecular level. We contribute to this effort by including the analysis of RNA editing. We extracted samples with the highest vs. lowest Epithelial score from two PM cohorts and observed increased RNA editing in introns and decreased RNA editing in 3'UTR upon EMT. The same was observed in primary PM primary cultures stratified by transcriptomics analysis into two groups, one of them enriched with mesenchymal features. Our data demonstrate that, as has been observed in other cancer types, RNA editing associates to EMT phenotype in PM.

Objectives: BAP1, CDKN2A, and NF2 are the most frequently altered genes in pleural mesotheliomas (PM). Discriminating PM from benign mesothelial proliferation (BMP) is sometimes challenging; it is well established that BAP1 loss, determined by immunohistochemistry (IHC), and CDKN2A homozygous deletion (HD), determined by fluorescence in situ hybridization (FISH), are useful. However, data regarding the diagnostic utility of NF2 FISH in PM is limited. Thus, we performed a multi-institutional study examining the utility of NF2 alterations determined by FISH for diagnosing PM in combination with BAP1 loss and CDKN2A HD., Materials and Methods: Multi-institutional PM cases, including 106 surgical and 107 cell block samples as well as 37 tissue cases of benign mesothelial proliferation (BMP) and 31 cell block cases with reactive mesothelial cells (RMC), were collected and analyzed using IHC for BAP1 and FISH for CDKN2A and NF2., Results: In PM, NF2 FISH revealed hemizygous loss (HL) in 54.7% of tissue cases (TC) and 49.5% of cell block cases (CBC), with about 90% of HL being monosomy. CDKN2A HD or BAP1 loss were detected in 75.5%/65.4% TC or 63.6%/60% CBC, respectively. BMP or RMC showed no BAP1 loss, CDKN2A HD, or NF2 HL. For discriminating PM from BMP, a combination of BAP1 loss, CDKN2A HD, and NF2 HL yielded enhanced sensitivity of 98.1% TC/94.4% CBC. BAP1 loss, CDKN2A HD, or NF2 HL were observed in 69%, 70%, or 58% of epithelioid PM, but in 9%, 91%, or 27% of sarcomatoid PM, respectively. Histotype, histological gradings, and CDKN2A deletion status showed significant differences in overall survival, while BAP1 loss and NF2 HL did not., Conclusion: NF2 HL, consisting predominantly of monosomy, can be detected by FISH in both TC and CBC of PM, and is effective for distinguishing PM from BMP, especially when combined with BAP1 loss and CDKN2A HD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is a rare understudied cancer associated with exposure to asbestos. So far, MPM patients have benefited marginally from the genomics medicine revolution due to the limited size or breadth of existing molecular studies. In the context of the MESOMICS project, we have performed the most comprehensive molecular characterization of MPM to date, with the underlying dataset made of the largest whole-genome sequencing series yet reported, together with transcriptome sequencing and methylation arrays for 120 MPM patients., Results: We first provide comprehensive quality controls for all samples, of both raw and processed data. Due to the difficulty in collecting specimens from such rare tumors, a part of the cohort does not include matched normal material. We provide a detailed analysis of data processing of these tumor-only samples, showing that all somatic alteration calls match very stringent criteria of precision and recall. Finally, integrating our data with previously published multiomic MPM datasets (n = 374 in total), we provide an extensive molecular phenotype map of MPM based on the multitask theory. The generated map can be interactively explored and interrogated on the UCSC TumorMap portal (https://tumormap.ucsc.edu/?p=RCG&#95;MESOMICS/MPM&#95;Archetypes )., Conclusions: This new high-quality MPM multiomics dataset, together with the state-of-art bioinformatics and interactive visualization tools we provide, will support the development of precision medicine in MPM that is particularly challenging to implement in rare cancers due to limited molecular studies., (© World Health Organization, [2023]. All rights reserved. The World Health Organization has granted the Publisher permission for the reproduction of this article.)

Pleural mesothelioma (PM) is a rare and aggressive disease that arises from the mesothelial cells lining the pleural cavity. Approximately 80% of PM patients have a history of asbestos exposure. The long latency period of 20-40 years from the time of asbestos exposure to diagnosis, suggests that multiple somatic genetic alterations are required for the tumorigenesis of PM. The genomic landscape of PM has been characterized by inter- and intratumor heterogeneity associated with the impairment of tumor suppressor genes such as CDKN2A , NF2 , and BAP1 . Current systemic therapies have shown only limited efficacy, and none is approved for patients with relapsed PM. Advances in understanding of the molecular landscape of PM has facilitated several biomarker-driven clinical trials but so far, no predictive biomarkers for targeted therapies are in clinical use. Recent advances in the PM genetics have provided optimism for successful molecular strategies in the future. Here, we summarize the molecular mechanism underlying PM pathogenesis and review potential therapeutic targets.