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PURPOSE: Pleomorphic xanthoastrocytoma (PXA) is an uncommon astrocytoma that tends to occur in children and young adults and has a relatively favorable prognosis. The 2021 WHO classification of tumors of the central nervous system (CNS WHO), 5th edition, rates PXAs as grade 2 and grade 3. The histological grading was based on mitotic activity (≥2.5 mitoses/mm2). This study specifically evaluates the clinical, morphological, and, especially, the molecular characteristics of grade 2 and 3 PXAs. METHODS: Between 2003 and 2021, we characterized 53 tumors with histologically defined grade 2 PXA (n = 36, 68%) and grade 3 PXA (n = 17, 32%). RESULTS: Compared with grade 2 PXA, grade 3 PXA has a deeper location and no superiority in the temporal lobe and is more likely to be accompanied by peritumoral edema. In histomorphology, epithelioid cells and necrosis were more likely to occur in grade 3 PXA. Molecular analysis found that the TERT promoter mutation was more prevalent in grade 3 PXA than in grade 2 PXA (35% vs. 3%; p = 0.0005) and all mutation sites were C228T. The cases without BRAF V600E mutation or with necrosis in grade 3 PXA had a poor prognosis (p = 0.01). CONCLUSION: These data define PXA as a heterogeneous astrocytoma. Grade 2 and grade 3 PXAs have different clinical and histological characteristics as well as distinct molecular profiles. TERT promoter mutations may be a significant genetic event associated with anaplastic progression. Necrosis and BRAF V600E mutation play an important role in the prognosis of grade 3 PXA.
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Astrocitoma , Proteínas Proto-Oncogénicas B-raf , Niño , Adulto Joven , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Astrocitoma/genética , Astrocitoma/patología , Mutación , PronósticoRESUMEN
BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a suicide enzyme that repairs the mispairing base O6-methyl-guanine induced by environmental and experimental carcinogens. It can transfer the alkyl group to a cysteine residue in its active site and became inactive. The chemical carcinogen N-nitroso compounds (NOCs) can directly bind to the DNA and induce the O6-methylguanine adducts, which is an important cause of gene mutation and tumorigenesis. However, the underlying regulatory mechanism of MGMT involved in NOCs-induced tumorigenesis, especially in the initiation phase, remains largely unclear. AIM: To investigate the molecular regulatory mechanism of MGMT in NOCs-induced gastric cell malignant transformation and tumorigenesis. METHODS: We established a gastric epithelial cell malignant transformation model induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or N-methyl-N-nitroso-urea (MNU) treatment. Cell proliferation, colony formation, soft agar, cell migration, and xenograft assays were used to verify the malignant phenotype. By using quantitative real-time polymerase chain reaction (qPCR) and Western blot analysis, we detected the MGMT expression in malignant transformed cells. We also confirmed the MGMT expression in early stage gastric tumor tissues by qPCR and immunohistochemistry. MGMT gene promoter DNA methylation level was analyzed by methylation-specific PCR and bisulfite sequencing PCR. The role of MGMT in cell malignant transformation was analyzed by colony formation and soft agar assays. RESULTS: We observed a constant increase in MGMT mRNA and protein expression in gastric epithelial cell malignant transformation induced by MNNG or MNU treatment. Moreover, we found a reduction of MGMT gene promoter methylation level by methylation-specific PCR and bisulfite sequencing PCR in MNNG/MNU-treated cells. Inhibition of the MGMT expression by O6-benzylguanine promoted the MNNG/MNU-induced malignant phenotypes. Overexpression of MGMT partially reversed the cell malignant transformation process induced by MNNG/MNU. Clinical gastric tissue analysis showed that MGMT was upregulated in the precancerous lesions and metaplasia tissues, but downregulated in the gastric cancer tissues. CONCLUSION: Our finding indicated that MGMT upregulation is induced via its DNA promoter hypomethylation. The highly expressed MGMT prevents the NOCs-induced cell malignant transformation and tumorigenesis, which suggests a potential novel approach for chemical carcinogenesis intervention by regulating aberrant epigenetic mechanisms.
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Sarcomatoid malignant mesothelioma (MM) is a rare and aggressive disease, and its diagnosis is challenging. A 60-year-old man presented with a recurrent subcutaneous mass in his right back after the initial resection. A chest computed tomography (CT) scan found right pleural thickening, nodular pleural thickening, pleural effusion, mediastinal, and right infraclavicular lymph nodes enlargement, which indicated a right pleura MM. Immunohistochemical stains of the resected mass showed sarcomatous atypical spindle cells, which were positive for pan-CKs (clone Anti-cytokeratin cocktail AE1/AE3), cytokeratin 5/6 (CK5/6), Wilm's tumor 1, podoplanin, vimentin and programmed death-ligand 1 (PD-L1), and negative for Napsin A, thyroid transcription factor 1, CDX 2, calretinin and desmin, and fluorescent in situ hybridization detected homozygous p16/cyclin-dependent kinase inhibitor 2A (p16/CDKN2A) deletion. The association of the chest CT features and the pathological assessment confirmed metastatic MM in the subcutaneous layer of the back. Moreover, positron emission tomography-CT showed multiple metastases in his brain. He developed massive right pleural effusion and chest tightness soon, and the mass kept growing despite local and systemic treatments. The patient die of pulmonary failure in 3 months.
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Mesotelioma Maligno/diagnóstico , Neoplasias Pleurales/patología , Insuficiencia Respiratoria/etiología , Neoplasias Cutáneas/diagnóstico , Tejido Subcutáneo/patología , Dorso , Biomarcadores de Tumor/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Resultado Fatal , Eliminación de Gen , Humanos , Imagen por Resonancia Magnética , Masculino , Mesotelioma Maligno/complicaciones , Mesotelioma Maligno/genética , Mesotelioma Maligno/secundario , Persona de Mediana Edad , Pleura/diagnóstico por imagen , Pleura/patología , Neoplasias Pleurales/complicaciones , Neoplasias Pleurales/diagnóstico , Neoplasias Pleurales/genética , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/secundario , Tejido Subcutáneo/diagnóstico por imagenRESUMEN
BACKGROUND: The monocarboxylate transporter (MCT) family especially MCT1 and MCT4 have been recognized to play an important role in lactate transport, a key glycolytic product. The expression of MCT1 and MCT4 expression was previously found to be related to poor outcome in various cancer types. In this study, we investigated the expression status of MCT1 and MCT4 and their relationship with prognosis in non-small cell lung cancer (NSCLC). METHODS: Expression of MCT4 and MCT1 in NSCLC tumor and adjacent lung tissues were detected by immunohistochemistry. Kaplan-Meier plots were used to evaluate two proteins' prognostic role, and the log-rank test obtained the P value. For multivariate analysis, the Cox proportional-hazards regression method was performed. RESULTS: High MCT4 and MCT1 expression was observed in cancer cells, with a rate of 45% for MCT4 versus 15% for MCT1 among all NSCLC patients. High expression of MCT4, and not MCT1, was associated with worse overall survival (OS) [hazard ratio (HR) =1.96 (1.06-3.75), P=0.032] and progression-free survival (PFS) [HR =1.72 (1.05-2.93), P=0.032] in NSCLC patients. In our multivariate analysis, advanced cancer stage and high MCT4 level were identified as independent predictive indicators for both PFS [HR(MCT4) =1.888 (1.114-3.199), P=0.018 and OS [HR (MCT4) =2.421 (1.271-4.610), P=0.007]. Subgroup and interaction analyses were also performed in different clinical characteristic groups and no significant differences were observed. CONCLUSIONS: High MCT4 expression is a predictive marker for worse outcome in NSCLC patients.
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Acute lymphoblastic leukemia (ALL) as a common cancer is a heterogeneous disease which is mainly divided into BCP-ALL and T-ALL, accounting for 80-85% and 15-20%, respectively. There are many differences between BCP-ALL and T-ALL, including prognosis, treatment, drug screening, gene research and so on. In this study, starting with methylation and gene expression data, we analyzed the molecular differences between BCP-ALL and T-ALL and identified the multi-omics signatures using Boruta and Monte Carlo feature selection methods. There were 7 expression signature genes (CD3D, VPREB3, HLA-DRA, PAX5, BLNK, GALNT6, SLC4A8) and 168 methylation sites corresponding to 175 methylation signature genes. The overall accuracy, accuracy of BCP-ALL, accuracy of T-ALL of the RIPPER (Repeated Incremental Pruning to Produce Error Reduction) classifier using these signatures evaluated with 10-fold cross validation repeated 3 times were 0.973, 0.990, and 0.933, respectively. Two overlapped genes between 175 methylation signature genes and 7 expression signature genes were CD3D and VPREB3. The network analysis of the methylation and expression signature genes suggested that their common gene, CD3D, was not only different on both methylation and expression levels, but also played a key regulatory role as hub on the network. Our results provided insights of understanding the underlying molecular mechanisms of ALL and facilitated more precision diagnosis and treatment of ALL.