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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.
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Acrilamidas , Compuestos de Anilina , Antineoplásicos , Neoplasias Encefálicas , Receptores ErbB , Gefitinib , Neoplasias Pulmonares , Mutación , Neoplasias Pleurales , Humanos , Masculino , Compuestos de Anilina/uso terapéutico , Acrilamidas/uso terapéutico , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Gefitinib/uso terapéutico , Receptores ErbB/genética , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Antineoplásicos/uso terapéutico , Neoplasias Pleurales/secundario , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/genética , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Progresión de la Enfermedad , Resultado del Tratamiento , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/secundario , Indoles , PirimidinasRESUMEN
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.
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Biomarcadores de Tumor , Inmunohistoquímica , Hibridación Fluorescente in Situ , Osteosarcoma , Neoplasias Pleurales , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pleurales/patología , Neoplasias Pleurales/genética , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Osteosarcoma/patología , Osteosarcoma/genética , Osteosarcoma/química , Diagnóstico Diferencial , Resultado FatalRESUMEN
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.
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Mesotelioma , Terapia Molecular Dirigida , Neoplasias Pleurales , Medicina de Precisión , Humanos , Medicina de Precisión/métodos , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Terapia Molecular Dirigida/métodos , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma/metabolismo , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Mesotelioma Maligno/tratamiento farmacológico , Mesotelioma Maligno/patología , Mesotelioma Maligno/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismoRESUMEN
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.
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Fusión Génica , Mesotelioma , Neoplasias Pleurales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Mesotelioma/genética , Mesotelioma/patología , Anciano , Adulto , Neoplasias Peritoneales/genética , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , PronósticoRESUMEN
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_circ_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_circ_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_circ_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.
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Biomarcadores de Tumor , Vesículas Extracelulares , Mesotelioma , ARN Circular , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Mesotelioma/genética , Mesotelioma/diagnóstico , Línea Celular Tumoral , Neoplasias Pleurales/genética , Neoplasias Pleurales/diagnóstico , Regulación Neoplásica de la Expresión Génica , Mesotelioma Maligno/genética , Mesotelioma Maligno/diagnósticoRESUMEN
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.
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Inhibidor p16 de la Quinasa Dependiente de Ciclina , Inmunohistoquímica , Mesotelioma , Neoplasias Pleurales , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Asbestos Anfíboles , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Eliminación de Gen , Homocigoto , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma/inducido químicamente , Mesotelioma/metabolismo , Mesotelioma Maligno/patología , Mesotelioma Maligno/genética , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Neoplasias Pleurales/inducido químicamente , Neoplasias Pleurales/metabolismo , Purina-Nucleósido Fosforilasa/genéticaRESUMEN
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.
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Factor 4G Eucariótico de Iniciación , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Biosíntesis de Proteínas , Proteínas Proto-Oncogénicas c-myc , ARN Largo no Codificante , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Mesotelioma Maligno/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factor 4G Eucariótico de Iniciación/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma/metabolismo , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Neoplasias Pleurales/metabolismo , Ribosomas/metabolismo , Ribosomas/genética , Estudios Retrospectivos , Pronóstico , Proliferación CelularRESUMEN
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.
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Mesotelioma Maligno , Neoplasias Pleurales , Proteína 28 que Contiene Motivos Tripartito , Humanos , Proteína 28 que Contiene Motivos Tripartito/metabolismo , Proteína 28 que Contiene Motivos Tripartito/genética , Pronóstico , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/genética , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo , Masculino , Femenino , Línea Celular Tumoral , Mesotelioma/genética , Mesotelioma/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Persona de Mediana Edad , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
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.
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Asbesto Crocidolita , Neoplasias Pleurales , Virus 40 de los Simios , Humanos , Virus 40 de los Simios/genética , China/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Pleurales/epidemiología , Neoplasias Pleurales/virología , Neoplasias Pleurales/genética , Mesotelioma/virología , Mesotelioma/epidemiología , Mesotelioma/genética , Infecciones por Polyomavirus/epidemiología , Infecciones Tumorales por Virus/epidemiología , Línea Celular Tumoral , Mesotelioma Maligno/genética , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiología , AdultoRESUMEN
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.
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Neoplasias Pleurales , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Neoplasias Pleurales/mortalidad , Mutación , Pérdida de Heterocigocidad , Mesotelioma/genética , Mesotelioma/patología , Adulto , Variaciones en el Número de Copia de ADN , Genómica/métodos , Biomarcadores de Tumor/genética , Pronóstico , Anciano de 80 o más Años , Mesotelioma Maligno/genética , Mesotelioma Maligno/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidadRESUMEN
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.
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Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Mesotelioma Maligno/complicaciones , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pleurales/genética , Mesotelioma/genética , Mesotelioma/diagnósticoRESUMEN
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.
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Amianto , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Mesotelioma/genética , Mesotelioma/diagnóstico , Neoplasias Pleurales/genética , Neoplasias Pulmonares/patologíaRESUMEN
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 G1/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 G1/S checkpoint in MPM cells. These findings suggest that POLD1 may be a novel therapeutic target in MPM.
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Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , ADN Polimerasa III/genética , Neoplasias Pulmonares/patología , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Mesotelioma/genética , ARN Interferente Pequeño/genética , Línea Celular Tumoral , Ciclo Celular/genética , Daño del ADN , ARN MensajeroRESUMEN
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.
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Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Biomarcadores de Tumor/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Homocigoto , Inmunohistoquímica , Hibridación Fluorescente in Situ , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma Maligno/genética , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Eliminación de Secuencia , Ubiquitina Tiolesterasa/genéticaRESUMEN
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.
Asunto(s)
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Pleura/patología , Mesotelioma/genética , Mesotelioma/patología , Mesotelioma Maligno/patología , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Perfilación de la Expresión GénicaRESUMEN
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 p16INK4a 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.
Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , Polvos/uso terapéutico , Proteína p53 Supresora de Tumor/genética , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/genética , Línea Celular Tumoral , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Cisplatino/farmacología , Cisplatino/uso terapéutico , Cisplatino/metabolismo , ADNRESUMEN
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.
Asunto(s)
Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Estudios Retrospectivos , Biomarcadores de Tumor/genética , Mutación , Mesotelioma/genética , Mesotelioma/cirugía , Neoplasias Pleurales/genética , Neoplasias Pleurales/cirugía , GenómicaRESUMEN
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.
Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Mesotelioma/genética , Mesotelioma/metabolismo , Fosfatidilinositol 3-Quinasas , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo , Neoplasias Pulmonares/patologíaRESUMEN
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.
Asunto(s)
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Pleurales , Humanos , Femenino , Mesotelioma/tratamiento farmacológico , Mesotelioma/genética , Mesotelioma/metabolismo , Estudios Retrospectivos , Inhibidores de Puntos de Control Inmunológico , Pronóstico , Receptor de Muerte Celular Programada 1 , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/genética , Neoplasias Pleurales/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , ARN Mensajero/genética , Biomarcadores de Tumor/análisisRESUMEN
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.