RESUMO
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.
Assuntos
Mesotelioma , Terapia de Alvo Molecular , Neoplasias Pleurais , Medicina de Precisão , Humanos , Medicina de Precisão/métodos , Neoplasias Pleurais/tratamento farmacológico , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Terapia de Alvo Molecular/métodos , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/patologia , Mesotelioma Maligno/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
Diffuse mesotheliomas are characterized by recurrent genomic alterations involving tumor suppressors and epigenetic regulators such as BAP1, CDKN2A, MTAP, and NF2. Depending on the differential diagnosis as informed by histologic assessment, one can apply the appropriate immunohistochemical and/or molecular panels to reach the correct pathologic diagnosis, sometimes even in cases with limited tissues. Biomarkers aid in the diagnosis of mesothelioma in the following scenarios: 1) For a tumor that is overtly malignant, how can one distinguish mesothelioma from other tumors? 2) For a mesothelial proliferation, how can one distinguish mesothelioma from a reactive process? To distinguish mesotheliomas from carcinomas, at least two positive and two negative markers are currently recommended. To distinguish sarcomatoid mesothelioma from pleomorphic carcinoma, even more markers-and sometimes molecular testing-are needed. To distinguish mesothelioma from reactive mesothelial conditions, useful immunohistochemical biomarkers include BAP1, MTAP, and merlin, which serve as surrogates for the corresponding gene mutation status. In patients with unusual clinical history, for tumors with a peculiar microscopic appearance, and/or in cases with an equivocal immunophenotypic profile, molecular testing can help to exclude mimics and to confirm the pathologic diagnosis.
Assuntos
Biomarcadores Tumorais , Mesotelioma , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mesotelioma/diagnóstico , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/metabolismo , Diagnóstico Diferencial , Patologia Molecular/métodos , Imuno-Histoquímica , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismoRESUMO
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.
Assuntos
Fusão Gênica , Mesotelioma , Neoplasias Pleurais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Mesotelioma/genética , Mesotelioma/patologia , Idoso , Adulto , Neoplasias Peritoneais/genética , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , PrognósticoRESUMO
We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 (BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1-silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.
Assuntos
Sinalização do Cálcio , Reparo do DNA , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Mesotelioma , Proteínas Supressoras de Tumor , Ubiquitina-Proteína Ligases , Humanos , Reparo do DNA/genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Mesotelioma/genética , Sinalização do Cálcio/genética , Feminino , Masculino , Pessoa de Meia-Idade , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Apoptose/genética , Fibroblastos/metabolismo , Amianto/toxicidade , Instabilidade GenômicaRESUMO
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.
Assuntos
Biomarcadores Tumorais , Vesículas Extracelulares , Mesotelioma , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mesotelioma/genética , Mesotelioma/diagnóstico , Linhagem Celular Tumoral , Neoplasias Pleurais/genética , Neoplasias Pleurais/diagnóstico , Regulação Neoplásica da Expressão Gênica , Mesotelioma Maligno/genética , Mesotelioma Maligno/diagnósticoAssuntos
Cistadenoma Papilar , Mesotelioma , Omento , Proteína Supressora de Tumor Von Hippel-Lindau , Humanos , Feminino , Cistadenoma Papilar/patologia , Cistadenoma Papilar/genética , Cistadenoma Papilar/diagnóstico , Cistadenoma Papilar/cirurgia , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Mesotelioma/patologia , Mesotelioma/genética , Omento/patologia , Omento/cirurgia , Mutação , Neoplasias Peritoneais/patologia , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/química , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/química , Imunofenotipagem , Diagnóstico Diferencial , Pessoa de Meia-Idade , Imuno-HistoquímicaRESUMO
Time-critical transcriptional events in the immune microenvironment are important for response to immune checkpoint blockade (ICB), yet these events are difficult to characterise and remain incompletely understood. Here, we present whole tumor RNA sequencing data in the context of treatment with ICB in murine models of AB1 mesothelioma and Renca renal cell cancer. We sequenced 144 bulk RNAseq samples from these two cancer types across 4 time points prior and after treatment with ICB. We also performed single-cell sequencing on 12 samples of AB1 and Renca tumors an hour before ICB administration. Our samples were equally distributed between responders and non-responders to treatment. Additionally, we sequenced AB1-HA mesothelioma tumors treated with two sample dissociation protocols to assess the impact of these protocols on the quality transcriptional information in our samples. These datasets provide time-course information to transcriptionally characterize the ICB response and provide detailed information at the single-cell level of the early tumor microenvironment prior to ICB therapy.
Assuntos
Carcinoma de Células Renais , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Mesotelioma , Microambiente Tumoral , Animais , Camundongos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , RNA-Seq , Análise de Sequência de RNA , Análise de Célula ÚnicaAssuntos
Mutação em Linhagem Germinativa , Síndrome de Li-Fraumeni , Neoplasias Peritoneais , Proteína Supressora de Tumor p53 , Humanos , Síndrome de Li-Fraumeni/genética , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/patologia , Proteína Supressora de Tumor p53/genética , Mesotelioma/genética , Mesotelioma/patologia , Feminino , Masculino , CriançaRESUMO
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.
Assuntos
Fator de Iniciação Eucariótico 4G , Regulação Neoplásica da Expressão Gênica , Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Biossíntese de Proteínas , Proteínas Proto-Oncogênicas c-myc , RNA Longo não Codificante , Humanos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Mesotelioma Maligno/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Fator de Iniciação Eucariótico 4G/genética , Fator de Iniciação Eucariótico 4G/metabolismo , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/metabolismo , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pleurais/metabolismo , Ribossomos/metabolismo , Ribossomos/genética , Estudos Retrospectivos , Prognóstico , Proliferação de CélulasRESUMO
BACKGROUND: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. METHODS: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. RESULTS: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vß-Jß rearrangements associated with MM immunotherapy efficacy. CONCLUSIONS: The present study reported the largest-scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR-specific clones.
Assuntos
Biomarcadores Tumorais , Mesotelioma Maligno , Humanos , Mesotelioma Maligno/genética , Masculino , Feminino , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Idoso , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Prognóstico , Genômica/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Adulto , Mesotelioma/genética , Mesotelioma/mortalidade , Mesotelioma/patologia , Imunoterapia/métodos , Linfócitos T/metabolismo , Linfócitos T/imunologiaRESUMO
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.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina , Imuno-Histoquímica , Mesotelioma , Neoplasias Pleurais , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Amiantos Anfibólicos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Deleção de Genes , Homozigoto , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/induzido quimicamente , Mesotelioma/metabolismo , Mesotelioma Maligno/patologia , Mesotelioma Maligno/genética , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pleurais/induzido quimicamente , Neoplasias Pleurais/metabolismo , Purina-Núcleosídeo Fosforilase/genéticaRESUMO
Mesothelial cells with reactive hyperplasia are difficult to distinguish from malignant mesothelioma cells based on cell morphology. This study aimed to identify and validate potential biomarkers that distinguish mesothelial cells from mesothelioma cells through machine learning combined with immunohistochemistry. It integrated the gene expression matrix from three Gene Expression Omnibus data sets (GSE2549, GSE12345, and GSE51024) to analyze the differently expressed genes between normal and mesothelioma tissues. Then, three machine learning algorithms, least absolute shrinkage and selection operator, support vector machine recursive feature elimination, and random forest were used to screen and obtain four shared candidate markers, including ACADL, EMP2, GPD1L, and HMMR. The receiver operating characteristic curve analysis showed that the area under the curve for distinguishing normal mesothelial cells from mesothelioma was 0.976, 0.943, 0.962, and 0.956, respectively. The expression and diagnostic performance of these candidate genes were validated in two additional independent data sets (GSE42977 and GSE112154), indicating that the performances of ACADL, GPD1L, and HMMR were consistent between the training and validation data sets. Finally, the optimal candidate marker ACADL was verified by immunohistochemistry assay. Acyl-CoA dehydrogenase long chain (ACADL) was stained strongly in mesothelial cells, especially for reactive hyperplasic mesothelial cells, but was negative in malignant mesothelioma cells. Therefore, ACADL has the potential to be used as a specific marker of reactive hyperplasic mesothelial cells in the differential diagnosis of mesothelioma.
Assuntos
Biomarcadores Tumorais , Biologia Computacional , Aprendizado de Máquina , Mesotelioma Maligno , Mesotelioma , Humanos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mesotelioma/genética , Mesotelioma/patologia , Mesotelioma/diagnóstico , Mesotelioma/metabolismo , Biologia Computacional/métodos , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/diagnóstico , Epitélio/metabolismo , Epitélio/patologiaRESUMO
Peritoneal mesothelioma (PeM) is an aggressive tumor with limited treatment options. The current study aimed to evaluate the value of next generation sequencing (NGS) of PeM samples in current practice. Foundation Medicine F1CDx NGS was performed on 20 tumor samples. This platform assesses 360 commonly somatically mutated genes in solid tumors and provides a genomic signature. Based on the detected mutations, potentially effective targeted therapies were identified. NGS was successful in 19 cases. Tumor mutational burden (TMB) was low in 10 cases, and 11 cases were microsatellite stable. In the other cases, TMB and microsatellite status could not be determined. BRCA1 associated protein 1 (BAP1) mutations were found in 32% of cases, cyclin dependent kinase inhibitor 2A/B (CDKN2A/B) and neurofibromin 2 (NF2) mutations in 16%, and ataxia-telangiectasia mutated serine/threonine kinase (ATM) in 11%. Based on mutations in the latter two genes, potential targeted therapies are available for approximately a quarter of cases (i.e., protein kinase inhibitors for three NF2 mutated tumors, and polyADP-ribose polymerase inhibitors for two ATM mutated tumors). Extensive NGS analysis of PeM samples resulted in the identification of potentially effective targeted therapies for about one in four patients. Although these therapies are currently not available for patients with PeM, ongoing developments might result in new treatment options in the future.
Assuntos
Neoplasias Pulmonares , Mesotelioma Maligno , Mesotelioma , Neoplasias Peritoneais , Humanos , Mesotelioma/diagnóstico , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Neoplasias Pulmonares/genética , Mutação , Genômica , Biomarcadores Tumorais/genética , Neoplasias Peritoneais/diagnóstico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genéticaRESUMO
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.
Assuntos
Mesotelioma Maligno , Neoplasias Pleurais , Proteína 28 com Motivo Tripartido , Humanos , Proteína 28 com Motivo Tripartido/metabolismo , Proteína 28 com Motivo Tripartido/genética , Prognóstico , Mesotelioma Maligno/metabolismo , Mesotelioma Maligno/genética , Neoplasias Pleurais/genética , Neoplasias Pleurais/metabolismo , Masculino , Feminino , Linhagem Celular Tumoral , Mesotelioma/genética , Mesotelioma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Pessoa de Meia-Idade , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologiaRESUMO
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.
Assuntos
Asbesto Crocidolita , Neoplasias Pleurais , Vírus 40 dos Símios , Humanos , Vírus 40 dos Símios/genética , China/epidemiologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Pleurais/epidemiologia , Neoplasias Pleurais/virologia , Neoplasias Pleurais/genética , Mesotelioma/virologia , Mesotelioma/epidemiologia , Mesotelioma/genética , Infecções por Polyomavirus/epidemiologia , Infecções Tumorais por Vírus/epidemiologia , Linhagem Celular Tumoral , Mesotelioma Maligno/genética , Neoplasias Pulmonares/virologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/epidemiologia , AdultoAssuntos
Mesotelioma , Humanos , Mesotelioma/diagnóstico , Mesotelioma/tratamento farmacológico , Mesotelioma/genética , Mesotelioma/cirurgia , Mesotelioma Maligno/diagnóstico , Mesotelioma Maligno/tratamento farmacológico , Mesotelioma Maligno/genética , Mesotelioma Maligno/cirurgia , Mutação , Medicina de Precisão/tendênciasRESUMO
Mesothelioma, an uncommon yet highly aggressive malignant neoplasm, presents challenges in the effectiveness of current therapeutic approaches. Ferroptosis, a non-apoptotic mechanism of cellular demise, exhibits a substantial association with the progression of diverse cancer forms. It is important to acknowledge that there exists a significant association between ferroptosis and the advancement of various forms of cancer. Nevertheless, the precise role of ferroptosis regulatory factors within the context of mesothelioma remains enigmatic. In our investigation, we initially scrutinized the prognostic significance of 24 ferroptosis regulatory factors in the realm of mesothelioma. Our observations unveiled that heightened expression levels of CARS1, CDKN1A, TFRC, FANCD2, FDFT1, HSPB1, SLC1A5, SLC7A11, coupled with reduced DPP4 expression, were indicative of an unfavorable prognosis. Built upon the nine previously discussed prognostic genes, the ferroptosis prognostic model offers a reliable means to forecast mesothelioma patients' survival with a substantial degree of precision. Furthermore, a notable correlation emerged between these prognostic ferroptosis regulators and parameters such as immune cell infiltration, tumor mutation burden, microsatellite instability, and PD-L1 expression in the context of mesothelioma. Within this cadre of nine ferroptosis regulatory factors with prognostic relevance, FANCD2 exhibited the most pronounced prognostic influence, as elucidated by our analyses. Subsequently, we executed a validation process employing clinical specimens sourced from our institution, thus confirming that heightened FANCD2 expression is a discernible harbinger of an adverse prognosis in the context of mesothelioma. In vitro experiments revealed that knocking down FANCD2 markedly suppressed the proliferation, migration, and ability of mesothelioma cells to attract immune cells. Furthermore, our findings also showed that reducing FANCD2 levels heightened the vulnerability of mesothelioma cells to inducers of ferroptosis. Furthermore, an extensive pan-cancer analysis uncovered a robust association between FANCD2 and the gene expression linked to immune checkpoints, thereby signifying an adverse prognosis across a broad spectrum of cancer types. Additional research is warranted to validate these findings.
Assuntos
Ferroptose , Regulação Neoplásica da Expressão Gênica , Mesotelioma , Ferroptose/genética , Humanos , Prognóstico , Mesotelioma/genética , Mesotelioma/patologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Linhagem Celular Tumoral , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Sistema y+ de Transporte de AminoácidosRESUMO
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.
Assuntos
Neoplasias Pleurais , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Neoplasias Pleurais/mortalidade , Mutação , Perda de Heterozigosidade , Mesotelioma/genética , Mesotelioma/patologia , Adulto , Variações do Número de Cópias de DNA , Genômica/métodos , Biomarcadores Tumorais/genética , Prognóstico , Idoso de 80 Anos ou mais , Mesotelioma Maligno/genética , Mesotelioma Maligno/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidadeRESUMO
BACKGROUND: More than half of mesothelioma tumours show alterations in the tumour suppressor gene BAP1. BAP1-deficient mesothelioma is shown to be sensitive to EZH2 inhibition in preclinical settings but only showed modest efficacy in clinical trial. Adding a second inhibitor could potentially elevate EZH2i treatment efficacy while preventing acquired resistance at the same time. METHODS: A focused drug synergy screen consisting of 20 drugs was performed by combining EZH2 inhibition with a panel of anti-cancer compounds in mesothelioma cell lines. The compounds used are under preclinical investigation or already used in the clinic. The synergistic potential of the combinations was assessed by using the Bliss model. To validate our findings, in vivo xenograft experiments were performed. RESULTS: Combining EZH2i with ATMi was found to have synergistic potential against BAP1-deficient mesothelioma in our drug screen, which was validated in clonogenicity assays. Tumour growth inhibition potential was significantly increased in BAP1-deficient xenografts. In addition, we observe lower ATM levels upon depletion of BAP1 and hypothesise that this might be mediated by E2F1. CONCLUSIONS: We demonstrated the efficacy of the combination of ATM and EZH2 inhibition against BAP1-deficient mesothelioma in preclinical models, indicating the potential of this combination as a novel treatment modality using BAP1 as a biomarker.