Biology subjects

Dreval, K.

Publications and source records attributed to Dreval, K..

5 recordsLinked to original sources

bioRxiv2025

LCR-modules: a collection of workflows for cancer genome analysis

The surge of genomic data from advanced sequencing technologies is outpacing current analytical pipelines. We introduce LCR-modules, an open-source suite of bioinformatics tools designed for flexible and automated cancer genome data analysis. LCR-modules enables reproducible analysis of diverse cancer genomics data at scale. The suite comprises 49 Snakemake-based workflows organized into three levels, facilitating tasks from low-level quality control to complex cohort-level analyses. LCR-modules supports various sequencing types and integrates pipelines such as mutation calling, expression quantification, and cohort-level aggregation, ensuring flexibility and reproducibility. LCR-modules represents a significant advancement in genomic data analysis, reducing barriers in reproducibility and scalability and has already been applied to a combination of exomes and genomes from over 10,800 samples.

bioinformatics↗

bioRxiv2025

The Origin, Diagnosis, and Prognosis of Oligomannose-Type Diffuse Large B Cell Lymphoma

The acquisition of N-glycosylation sites occupied by oligomannose-type glycans in the immunoglobulin complementarity-determining region (CDR) is an early clonal tumor-specific identifier of follicular lymphoma (FL). CDR-located N-glycosylation sites are also acquired in germinal-center-B-cell-like diffuse large B-cell lymphomas (GCB-DLBCL), but their significance is less defined. We used RNA-seq immunoglobulin assembly to determine the frequency and CDR location of the acquired N-glycosylation sites (AGS) in two large independent DLBCL cohorts. Composition of the glycans occupying the AGS was determined using liquid chromatography-mass spectrometry and correlated with cell-of-origin, FL signature (defined by EZB phenotype or BCL2 translocation), transcript profile, and clinical outcome. CDR-located AGS were observed in 41-46% of GCB-DLBCL but were rare in other DLBCL. Only CDR-located AGS of DLBCL with an FL signature were occupied by oligomannose-type glycans. These DLBCL were termed Mann-type DLBCL. Conversely, the AGS of the other DLBCL were either non-glycosylated or occupied by complex-type glycans. Mann-type status was an independent marker of short progression-free survival and overall survival. In contrast, the other GCB-DLBCL cases, including those with an FL signature but without AGS, had the best outcomes. Mann-type DLBCL overexpressed gene-sets of cell growth, survival, and cycling, and underexpressed proinflammatory and apoptotic pathways, irrespective of concomitant MYC translocations. Acquisition of Mann-type glycans is a highly selective environmental pressure, identifying the most aggressive GCB-DLBCL with an origin related to FL. The detection of AGS in the CDR of GCB-DLBCLs with a BCL2 translocation defines Mann-type DLBCLs, refines prognosis and marks a precise tumor interaction to block early therapeutically. Key pointsO_LIAcquisition of Mann-type glycans is a tumor-specific environmental pressure identifying the most aggressive GCB-DLBCL with an origin related to FL. C_LIO_LIMann-type DLBCL can be diagnosed by the concomitant detection of AGS in the CDR and a BCL2 translocation. C_LI

cancer biology↗

bioRxiv2023

Revisiting Reddy: A DLBCL Do-over

The 2017 study by Reddy et al described the comprehensive characterization of somatic drivers of diffuse large B-cell lymphoma using whole exome sequencing.1 After additional large studies relying on exome or whole genome sequencing were published, several oddities unique to the Reddy results have emerged. Seeking to explain the discrepancies, we reanalyzed their data using established open-source pipelines. This revealed thousands of mutations that could not be independently reproduced by these pipelines and a larger set of high-quality mutations that were not reported by Reddy. This caused an artificial under-representation of the mutation prevalence in many genes including clinically relevant hot spots affecting EZH2 and CD79B. More generally, the study had an under-representation of mutations in DLBCL genes that disproportionately affected genes known to have the highest mutation rates. The missing variants and the spurious variants can be attributed to distinct problems with the analytical approaches employed in that study. Our analysis also identified strong associations between mutations and patient outcome including TP53, KMT2D and PIM1, which were not found in the Reddy study. Overall, we demonstrate that this combination of errors influenced many of the central novel findings from their study rendering their results largely non-replicable. The full results of our analyses are included as supplemental items as a resource for other researchers with an interest in the genetics of B-cell lymphomas.

genomics↗

bioRxiv2021

Shared and distinct genetic features in human and canine B-cell lymphomas

Animal models of human cancers are an important tool for the development and preclinical evaluation of therapeutics. Canine B-cell lymphoma (cBCL) is an appealing model for human mature B-cell neoplasms due to the high sequence similarity in cancer genes to humans and inactive telomerase in adult tissues. We performed targeted sequencing on 86 canine patients from the Canine Comparative Oncology Genomic Consortium, with 61 confirmed as B-cell lymphomas. We confirmed a high frequency of mutations in TRAF3 (45%) and FBXW7 (20%) as has been reported by our group and others. We also note a higher frequency of DDX3X (20%) and MYC (13%) mutations in our canine cohort. We compared the pattern and incidence of mutations in cBCL to human diffuse large B-cell lymphoma (hDLBCL) and human Burkitt lymphoma (hBL). Canine MYC mutations displayed a focal pattern with 80% of mutations affecting the conserved phosphodegron sequence in MYC box 1, which are known to stabilize MYC protein. We also note that MYC and FBXW7 mutations do not co-occur in our cBCL cohort, leading to the hypothesis that these mutations represent alternative approaches to stabilize MYC in canine lymphoma. We observed striking differences in the pattern of DDX3X mutations in canine lymphoma as compared to hBL and uncovered a sex-specific pattern of DDX3X mutations in hBL that is not consistent with those identified in canine lymphomas. In sum, we describe key differences between cBCL and human mature B-cell lymphomas which may indicate differences in the biology of these cancers. This should be considered in future studies of cBCL as a model of human lymphomas.

cancer biology↗

bioRxiv2021

Non-coding NFKBIZ 3' UTR mutations promote cell growth and resistance to targeted therapies in diffuse large B-cell lymphoma

Amplifications and non-coding 3' UTR mutations affecting NFKBIZ have been identified as recurrent genetic events in diffuse large B-cell lymphoma (DLBCL). We confirm the prevalence and pattern of NFKBIZ 3' UTR mutations in independent cohorts and determine they are enriched in the ABC subtype as well as the recently described novel BN2/C1/NOTCH2 classes of DLBCL. Presently, the effects of and mechanism by which non-coding mutations can act as cancer drivers has been relatively unexplored. Here, we provide a functional characterization of these non-coding NFKBIZ 3' UTR mutations. We demonstrate that the resulting elevated expression of I{kappa}B-{zeta} confers growth advantage in DLBCL cell lines and primary germinal center B-cells as well as nominate novel I{kappa}B-{zeta} target genes with potential therapeutic implications. The limited responses to targeted treatments in DLBCL, particularly those targeting the NF-{kappa}B axis, led us to investigate and confirm that NFKBIZ 3' UTR mutations affect response to therapeutics and suggest it may be a useful predictive biomarker. Statement of SignificanceThrough functional characterization we reveal that non-coding NFKBIZ 3' UTR mutations are a common driver in DLBCL, and mutation status may be a relevant biomarker to predict poor response to therapeutics targeting the NF-{kappa}B pathway.

cancer biology↗