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Cancer Genomics & Proteomics 2023Mesotheliomas are tumors similar to, and probably derived from, mesothelial cells. They carry acquired chromosomal rearrangements, deletions affecting CDKN2A,...
BACKGROUND/AIM
Mesotheliomas are tumors similar to, and probably derived from, mesothelial cells. They carry acquired chromosomal rearrangements, deletions affecting CDKN2A, pathogenetic polymorphisms in NF2, and fusion genes which often contain the promiscuous EWSR1, FUS, and ALK as partner genes. Here, we report the cytogenomic results on two peritoneal mesotheliomas.
MATERIALS AND METHODS
Both tumors were examined using G-banding with karyotyping and array comparative genomic hybridization (aCGH). One of them was further investigated with RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), Sanger sequencing, and fluorescence in situ hybridization (FISH).
RESULTS
In the first mesothelioma, the karyotype was 25∼26,X,+5,+7,+20[cp4]/50∼52,idemx2[cp7]/46,XX[2]. aCGH detected gains of chromosomes 5, 7, and 20 with retained heterozygosity on these chromosomes. In the second tumor, the karyotype was 46,XX,inv(10)(p11q25)[7]/46,XX[3]. aCGH did not detect any gains or losses and showed heterozygosity for all chromosomes. RNA sequencing, RT-PCR/Sanger sequencing, and FISH showed that the inv(10) fused MAP3K8 from 10p11 with ABLIM1 from 10q25. The MAP3K8::ABLIM1 chimera lacked exon 9 of MAP3K8.
CONCLUSION
Our data, together with information on previously described mesotheliomas, illustrate two pathogenetic mechanisms in peritoneal mesothelioma: One pathway is characterized by hyperhaploidy, but with retained disomies for chromosomes 5, 7, and 20; this may be particularly prevalent in biphasic mesotheliomas. The second pathway is characterized by rearrangements of MAP3K8 from which exon 9 of MAP3K8 is lost. The absence of exon 9 from oncogenetically rearranged MAP3K8 is a common theme in thyroid carcinoma, lung cancer, and spitzoid as well as other melanoma subtypes.
Topics: Humans; In Situ Hybridization, Fluorescence; Comparative Genomic Hybridization; Mesothelioma, Malignant; Mesothelioma; Carcinogenesis; Cell Transformation, Neoplastic; Peritoneal Neoplasms; Microfilament Proteins; LIM Domain Proteins
PubMed: 37400148
DOI: 10.21873/cgp.20388 -
Cell Reports. Medicine Feb 2023Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. A better understanding of mesothelioma genomics and transcriptomics...
Malignant mesothelioma is an aggressive cancer with limited treatment options and poor prognosis. A better understanding of mesothelioma genomics and transcriptomics could advance therapies. Here, we present a mesothelioma cohort of 122 patients along with their germline and tumor whole-exome and tumor RNA sequencing data as well as phenotypic and drug response information. We identify a 48-gene prognostic signature that is highly predictive of mesothelioma patient survival, including CCNB1, the expression of which is highly predictive of patient survival on its own. In addition, we analyze the transcriptomics data to study the tumor immune microenvironment and identify synthetic-lethality-based signatures predictive of response to therapy. This germline and somatic whole-exome sequencing as well as transcriptomics data from the same patient are a valuable resource to address important biological questions, including prognostic biomarkers and determinants of treatment response in mesothelioma.
Topics: Humans; Mesothelioma, Malignant; Prognosis; Transcriptome; Lung Neoplasms; Mesothelioma; Genomics; Tumor Microenvironment
PubMed: 36773602
DOI: 10.1016/j.xcrm.2023.100938 -
International Journal of Molecular... Jul 2018Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular... (Review)
Review
Malignant mesothelioma (MM), a rare and severe cancer, mainly caused as a result of past-asbestos exposure, is presently a public health concern. Current molecular studies aim to improve the outcome of the disease, providing efficient therapies based on the principles of precision medicine. To model the molecular profile of human malignant mesothelioma, animal models have been developed in rodents, wild type animals and genetically engineered mice harbouring mutations in tumour suppressor genes, especially selecting genes known to be inactivated in human malignant mesothelioma. Animals were either exposed or not exposed to asbestos or to other carcinogenic fibres, to understand the mechanism of action of fibres at the molecular level, and the role of the selected genes in mesothelial carcinogenesis. The aim of the manuscript was to compare mesothelioma models to human malignant mesothelioma and to specify the clue genes playing a role in mesothelial carcinogenesis. Collectively, MM models recapitulate the clinical features of human MM. At least two altered genes are needed to induce malignant mesothelioma in mice. Two pathways regulated by and seem independent key players in mesothelial carcinogenesis. Other genes and pathways appear as bona fide modulators of the neoplastic transformation.
Topics: Animals; Animals, Genetically Modified; Carcinogenesis; Epithelium; Humans; Lung; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Mice; Mutation; Neoplasms, Experimental; Rats
PubMed: 30060470
DOI: 10.3390/ijms19082191 -
Cancer Immunology Research Oct 2023Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation...
Infiltration of tumor by T cells is a prerequisite for successful immunotherapy of solid tumors. In this study, we investigate the influence of tumor-targeted radiation on chimeric antigen receptor (CAR) T-cell therapy tumor infiltration, accumulation, and efficacy in clinically relevant models of pleural mesothelioma and non-small cell lung cancers. We use a nonablative dose of tumor-targeted radiation prior to systemic administration of mesothelin-targeted CAR T cells to assess infiltration, proliferation, antitumor efficacy, and functional persistence of CAR T cells at primary and distant sites of tumor. A tumor-targeted, nonablative dose of radiation promotes early and high infiltration, proliferation, and functional persistence of CAR T cells. Tumor-targeted radiation promotes tumor-chemokine expression and chemokine-receptor expression in infiltrating T cells and results in a subpopulation of higher-intensity CAR-expressing T cells with high coexpression of chemokine receptors that further infiltrate distant sites of disease, enhancing CAR T-cell antitumor efficacy. Enhanced CAR T-cell efficacy is evident in models of both high-mesothelin-expressing mesothelioma and mixed-mesothelin-expressing lung cancer-two thoracic cancers for which radiotherapy is part of the standard of care. Our results strongly suggest that the use of tumor-targeted radiation prior to systemic administration of CAR T cells may substantially improve CAR T-cell therapy efficacy for solid tumors. Building on our observations, we describe a translational strategy of "sandwich" cell therapy for solid tumors that combines sequential metastatic site-targeted radiation and CAR T cells-a regional solution to overcome barriers to systemic delivery of CAR T cells.
Topics: Humans; Mesothelin; Immunotherapy, Adoptive; GPI-Linked Proteins; Receptors, Antigen, T-Cell; Mesothelioma; Mesothelioma, Malignant; Receptors, Chemokine; Chemokines; Cell Line, Tumor
PubMed: 37540803
DOI: 10.1158/2326-6066.CIR-22-0840 -
Cancer Cytopathology Jul 2021Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition... (Review)
Review
Malignant mesothelioma is a rare malignancy with a poor prognosis whose development is related to asbestos fiber exposure. An increasing role of genetic predisposition has been recognized recently. Pleural biopsy is the gold standard for diagnosis, in which the identification of pleural invasion by atypical mesothelial cell is a major criterion. Pleural effusion is usually the first sign of disease; therefore, a cytological specimen is often the initial or the only specimen available for diagnosis. Given that reactive mesothelial cells may show marked atypia, the diagnosis of mesothelioma on cytomorphology alone is challenging. Accordingly, cell block preparation is encouraged, as it permits immunohistochemical staining. Traditional markers of mesothelioma such as glucose transporter 1 (GLUT1) and insulin-like growth factor 2 mRNA-binding protein 3 (IMP3) are informative, but difficult to interpret when reactive proliferations aberrantly stain positive. BRCA1-associated protein 1 (BAP1) nuclear staining loss is highly specific for mesothelioma, but sensitivity is low in sarcomatoid tumors. Cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16 homozygous deletion, assessed by fluorescence in situ hybridization, is more specific for mesothelioma with better sensitivity, even in the sarcomatoid variant. The surrogate marker methylthioadenosine phosphorylase (MTAP) has been found to demonstrate excellent diagnostic correlation with p16. The purpose of this review is to provide an essential appraisal of the literature regarding the diagnostic value of many of these emerging biomarkers for malignant mesothelioma in effusion cytology.
Topics: Biomarkers, Tumor; Homozygote; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Mesothelioma, Malignant; Pleural Effusion; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 33465294
DOI: 10.1002/cncy.22398 -
International Journal of Molecular... Sep 2020Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is... (Review)
Review
Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer of the mesothelial cells lining the pleural surface of the chest wall and lung. The etiology of MPM is strongly associated with prior exposure to asbestos fibers, and the median survival rate of the diagnosed patients is approximately one year. Despite the latest advancements in surgical techniques and systemic therapies, currently available treatment modalities of MPM fail to provide long-term survival. The increasing incidence of MPM highlights the need for finding effective treatments. Targeted therapies offer personalized treatments in many cancers. However, targeted therapy in MPM is not recommended by clinical guidelines mainly because of poor target definition. A better understanding of the molecular and cellular mechanisms and the predictors of poor clinical outcomes of MPM is required to identify novel targets and develop precise and effective treatments. Recent advances in the genomics and functional genomics fields have provided groundbreaking insights into the genomic and molecular profiles of MPM and enabled the functional characterization of the genetic alterations. This review provides a comprehensive overview of the relevant literature and highlights the potential of state-of-the-art genomics and functional genomics research to facilitate the development of novel diagnostics and therapeutic modalities in MPM.
Topics: Animals; Biomarkers, Tumor; Genomics; Humans; Mesothelioma, Malignant; Phenomics; Pleural Neoplasms
PubMed: 32882916
DOI: 10.3390/ijms21176342 -
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 -
Journal of Thoracic Oncology : Official... Dec 2022
Topics: Humans; Lung Neoplasms; Mesothelioma, Malignant; Heart Neoplasms; Heart
PubMed: 36410967
DOI: 10.1016/j.jtho.2022.09.224 -
Modern Pathology : An Official Journal... Oct 2022BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural...
BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.
Topics: Biomarkers, Tumor; Diagnosis, Differential; Humans; Immunohistochemistry; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neurofibromin 2; Pleural Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Ubiquitin Thiolesterase
PubMed: 35459788
DOI: 10.1038/s41379-022-01081-z -
Journal of Thoracic Oncology : Official... Nov 2021
Topics: Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms; Risk Factors
PubMed: 34716000
DOI: 10.1016/j.jtho.2021.07.010