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.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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.
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.
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.
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.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Keywords: MALT lymphoma; marginal zone lymphoma; extra-nodal lymphoma; DNA methylation; lymphoma progression Summary 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 (I/I.sub.max ayen0*4, q less than or equal to 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. Article Note: R.D. and R.W. contributed equally to the work. CAPTION(S): Fig S1. Histology and Ki-67 immunohistochemical staining of MZBL. Fig S2. Scatterplot displaying the DNA methylation level of 822908 loci for the three paired samples. Fig S3. Phylogenetic tree based on the DNA methylation pattern of 1302 CpGs loci described to become differentially methylated during B-cell development. Fig S4. Comparison of the DNA methylation profile during MZBL progression. Fig S5. DNA methylation profile of germinal centre B cell (gcBC), naive B cell (naiBC) and benign T cell at loci identified to be significantly differentially methylated between the SC- and the LC-MZBL. Fig S6. DNA methylation profile of gastric mucosa samples infected with Helicobacter pylori at loci identified to be significantly differentially methylated between the SC- and the LC-MZBL. Fig S7. Supervised analysis between the SC-MZBL and benign samples. Fig S8. Haematoxylin and eosin and immunohistochemistry staining for Ki-67 for Com(SC+LC) lymphoma. Fig S9. Haematoxylin and eosin and immunohistochemical staining for Ki-67 of Com(SC+LC)-3 lymphoma. Fig S10. Relative distribution of the loci differentially methylated during MALT lymphoma progression between SC- and LC-MZBL. Fig S11. Relative distribution of the loci differentially methylated during MALT lymphoma progression between the SC- and LC-MZBL. Fig S12. Integrated analysis of differentially methylated and differentially expressed genes in LC- in comparison to SC-MZBL. Data S1. Supplemental methods. Table SI. Case identifiers for the study cohort. Table SII. Overview on the features of the analysed gastric MZBL cases, benign T cells and benign gastric mucosa infected with Helicobacter pylori. Table SIII. Overview of the analysed B-cell populations of various differentiation stages. Table SIV. Enrichment analysis of differentially methylated loci between SC- and LC-MZBL for Polycomb repressive complex target regions and Kulis Modules.1 Table SV. Pathway enrichment analysis of differentially methylated loci between the SC- and the LC-MZB using PANTHER (i) and g:Profiler (ii). Table SVI. Integrated analysis of DNA methylation and gene expression data: 53 genes are differentially expressed and differentially methylated between SC- and LC-MZBL. Table SVII. Expression of CDCA8 protein detected by immunohistochemistry. Byline: Rucha Dugge, Rabea Wagener, Peter MOs.ller, Thomas F. E. Barth
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Summary
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.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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