RESUMO
Extra-nodal marginal zone B-cell lymphoma (MZBL) of mucosa-associated lymphoid tissue is an indolent lymphoma mostly affecting the gastrointestinal tract. The lymphoma initially has small-cell morphology (SC-MZBL) and often arises in the background of Helicobacter pylori-induced gastritis. In some cases, a clonal malignant progression to large-cell morphology (LC-MZBL) is observed. Here, we studied the DNA methylation profile of 30 gastric MZBLs along their progression. Genome-wide DNA methylation profiling, identified 7698 significantly differentially methylated loci during gastric MZBL progression (σ/σmax ≥0·4, q ≤ 0·001). LC-MZBL showed hypermethylation in comparison to SC-MZBL with an enrichment of regions involved in transcriptional regulation. In conclusion, our present data show that the morphological distinction between SC- and LC-MZBL is reflected by characteristic DNA methylation profiles.
Assuntos
Gastrite/etiologia , Infecções por Helicobacter/complicações , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma não Hodgkin/genética , Neoplasias Gástricas/genética , Linfócitos B/patologia , Metilação de DNA , Progressão da Doença , Extensão Extranodal/patologia , Gastrite/microbiologia , Estudo de Associação Genômica Ampla , Humanos , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/patologia , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologiaAssuntos
Artrite Reumatoide , Leucemia Mielogênica Crônica BCR-ABL Positiva , Linfoma de Células T , Granulomatose Linfomatoide , Metotrexato/efeitos adversos , Segunda Neoplasia Primária , Idoso , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Linfoma de Células T/induzido quimicamente , Linfoma de Células T/patologia , Granulomatose Linfomatoide/induzido quimicamente , Granulomatose Linfomatoide/patologia , Masculino , Metotrexato/administração & dosagem , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/patologiaRESUMO
Primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) is a heterogeneous subgroup of DLBCL. We investigated the prevalence and prognostic value of surface expression of PD-L1, PD1, and CD30, copy number of 9p24.1 (PD-L1 region), and mutations in MYD88, CD79B, CARD11, and BTK in a cohort of 116 patients, localized in the mediastinum (PMBL, n = 12), ear, nose and throat (ENT, n = 28), central nervous system (n = 29), testis (n = 7), breast (n = 4), stomach (n = 10), bone (n = 8), spleen (n = 2), and skin (n = 16). PD-L1 expression is most frequent in PMBL (92%), followed by lymphomas originating in the stomach (57%), ENT (23%), and skin (18%). PD1 was expressed at low levels in less than 13% of PE-DLBCL, while CD30 expression was found in 58% of PMBL. Mutation analysis revealed an unexpectedly high frequency of MYD88 and CD79B mutations in ENT lymphomas (46% and 50%, respectively). CARD11 mutations are rare but more frequently found in gastric lymphomas (30%), suggesting BTK resistance. Thirty-four of 113 (30%) of the lymphomas harbored both MYD88 and CD79B mutations. Lower overall and progression-free survival rates were found for cases with MYD88, CD79B, and BTK mutations. These data confirm the biologic singularity of PE-DLBCLs and provide some suggestions for targeted therapies.
RESUMO
BACKGROUND: To elucidate the role of iPLA2/PLA2G6 in gingivobuccal squamous cell carcinoma (GB-SCC) and to ascertain the synthetic lethality-based chemoprevention role of aspirin in arachidonic acid metabolism (AAM) pathway down-regulated GB-SCC. METHODS: The in vitro efficacy of aspirin on GB-SCC cells (ITOC-03 and ITOC-04) was assessed by cell proliferation, colony formation, apoptosis, cell migration, cell cycle assay and RNA-seq, while inhibition of PLA2G6 and AAM pathway components was affirmed by qPCR, Western blot and immunofluorescence staining. The in vivo effect of aspirin was evaluated using NOD-SCID mice xenografts and immunohistochemical analysis. RESULTS: We found that aspirin, which has been reported to act through the COX pathway, is inhibiting PLA2G6, and thereby the COX and LOX components of the AAM pathway. The findings were validated using PLA2G6 siRNA and immunohistochemical marker panel. Moreover, a pronounced effect in ITOC-04 cells and xenografts implied aspirin-induced synthetic lethality in the AAM pathway down-regulated GB-SCC. CONCLUSIONS: This study reveals that aspirin induces the anti-tumor effect by a previously unrecognized mechanism of PLA2G6 inhibition. In addition, the effect of aspirin is influenced by the baseline AAM pathway status and could guide precision prevention clinical trials of AAM pathway inhibitors.