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Diffuse large B‐cell lymphoma (DLBCL) and follicular lymphoma (FL) are two of the most prevalent non‐Hodgkin's lymphoma subtypes. Despite advances, treatment resistance and patient relapse remain challenging issues. Our study aimed to scrutinize gene expression distinctions between DLBCL and FL, employing a cohort of 53 DLBCL and 104 FL samples that underwent rigorous screening for genetic anomalies. The NanoString nCounter assay evaluated 730 cancer‐associated genes, focusing on densely tumorous areas in diagnostic samples. Employing the Lymph2Cx method, we determined the cell‐of‐origin (COO) for DLBCL cases. Our meticulous analysis, facilitated by Qlucore Omics Explorer software, unveiled a substantial 37% of genes with significantly differential expression patterns between DLBCL and FL, pointing to nuanced mechanistic disparities. Investigating the impact of FL disease stage and DLBCL COO on gene expression yielded minimal differences, prompting us to direct our attention to consistently divergent genes in DLBCL. Intriguingly, our Gene Set Enrichment Analysis spotlighted 21% of these divergent genes, converging on the DNA damage response (DDR) pathway, vital for cell survival and cancer evolution. Strong positive correlations among most DDR genes were noted, with key genes like BRCA1, FANCA, FEN1, PLOD1, PCNA, and RAD51 distinctly upregulated in DLBCL compared to FL and normal tissue controls. These findings were subsequently validated using RNA seq data on normal controls and DLBCL samples from public databases like The Cancer Genome Atlas (TCGA) and the Genotype‐Tissue Expression (GTEx) databases, enhancing the robustness of our results. Considering the established significance of these DDR genes in solid cancer therapies, our study underscores their potential applicability in DLBCL treatment strategies. In conclusion, our investigation highlights marked gene expression differences between DLBCL and FL, with particular emphasis on the essential DDR pathway. The identification of these DDR genes as potential therapeutic targets encourages further exploration of synthetic lethality‐based approaches for managing DLBCL. [ABSTRACT FROM AUTHOR]

Introduction: Detection of DNA mutations in acute myeloid leukemia (AML) has important implications for disease diagnosis, treatment protocols, disease progression, and more. With the advent of next-generation sequencing (NGS), researchers, clinical scientists, and medical practitioners can gain valuable insight into the molecular nature of different diseases. Targeted DNA sequencing panels are gaining popularity in translational research settings to provide real-time information to guide clinical decision-making. Here, we present the somatic mutation landscape analysis of 545 AMLs sequenced from 2017-2023. Methods: DNA extracted from bone marrow / peripheral blood specimens with high blast count was sequenced using Trusight 54 gene panel on Illumina Miseq Next-generation Sequencing platform. Primary and secondary bioinformatics analysis was performed using Sophia Genetics DDM software. Results: We identified 1899 DNA mutations of clinical significance in 54 pathogenic genes implicated in myeloid malignancies. The top five most common mutated genes included TET2 (27%), ASXL1 (26%), DNMT3A (25%), NPM1 (19%), and RUNX1 (17%). Somatic interaction analysis highlighted several combinations of co-occurring mutations including DNMT3A and NPM1, FLT3 and NPM1, and RUNX1 and SRSF2. We identified classic mutational patterns such as oncogenic hotspots and one-hit knock-out of tumor suppressor genes. Analysis using the Drug Gene Interaction Database identified 16 mutated genes with clinical actionability, which included ASXL1, BCOR, BCORL1, DNMT3A, and FLT3. Conclusion: NGS Myeloid panel provides an effective platform for comprehensive genomic profiling and identification of mutations with biological and clinical significance in AMLs. Using this targeted sequencing approach in combination with mutational analysis allows cutting-edge technologies to become increasingly available to patients with cancer, which may consequently improve disease survival rates and patient quality of life. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive disease with frequent relapse. Targeted therapies against B-cell receptor (BCR) molecules have demonstrated improved outcomes in relapsed cases. However, clinical responses are slow and selective, with failure to attain complete remission in a significant subset of patients. Complex interaction of BCR signal transduction with toll-like receptor (TLR) and other pathways in MCL remains unknown, thus averting progress in development of targeted therapies. We have performed detailed digital quantification of BCR/TLR signalling molecules and their effector pathways in a cohort (n = 81) of MCL patients and correlated these data with overall survival. Hierarchical clustering model based on BCR/TLR genes revealed two distinct (BCRhigh and BCRlow ) subsets of patients (n = 32; 40%) with significant differences in expression (>1.5-fold change; p < 0.05). Higher levels of BTK/SYK/BLNK/CARD11/PLCG signalosome and lower expression of MALT1/BCL10 genes suggested tonic pattern of BCR activation. Amplified expression of TLR6/TLR7/TLR9 was noted in concert with hyper-responsiveness of BCR machinery. MYD88, a key TLR adaptor molecule, was not upregulated in any of these clusters, which may suggest a 'cross-talk' between BCR and TLR pathways. In sync with BCR/TLR signalling, we recorded significantly enhanced expression of genes associated with NF-kB pathway in BCRhigh subset of MCL patients. On univariate analysis, the BCRhigh patients showed a trend towards inferior clinical response to a standardized treatment protocol, compared with the BCRlow group (log rank, p = 0.043). In conclusion, we have identified hyperactive BCR/TLR signalling pathways and their effector downstream targets in a subset of MCL patients and associated it with poor clinical outcomes. Our study provides quantitative evidence at RNA expression level of possible concomitant collaboration between TLR and BCR signalling molecules in MCL. These data will provide further insights for future functional studies and, hence, development of targeted therapies for MCL patients. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) is an aggressive disease with poor overall survival, attributable in part to frequent defects of the DNA repair genes. In such malignancies, additional inhibition of the ubiquitous DNA damage repair protein, poly-ADP ribose polymerase-1 (PARP1) has shown enhanced cytotoxicity (so-called synthetic lethality). We studied PARP1 expression in a series of clinical cases of MCL, with the secondary aim to ascertain the relationship between PARP1 expression and DNA repair gene expression (namely ATM and p53) by immunohistochemical methods. We also examined the relationship between PARP1 expression and the well-established prognostic biomarker Ki-67, in addition to correlating PARP1 expression with the overall survival. From amongst our series of 79 unselected cases of MCL, we detected PARP1 expression in all but two cases with variable intensity. We also noted correlations between PARP1 expression and ATM and p53 expression. As described in previous studies, we identified a significant survival difference on the basis of Ki-67 and p53 expression. When digital H-score analysis of PARP1 expression was performed, there was a distinct survival advantage noted in patients with lower levels of expression. When our biomarker data were assessed by Cox regression, furthermore, the dominant effects of p53 and PARP1 expression were highlighted. Our data support the need for further research into the potential utility of PARP1 as a biomarker in MCL and for the potential direction of future PARP1 inhibitor-targeted therapy studies. [ABSTRACT FROM AUTHOR]