Project description:<p>Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogenous disease that is further classified into transcriptionally defined activated B-cell (ABC) and germinal center B-cell (GCB) subtypes. Here, we describe a comprehensive genetic analysis of DLBCLs that identifies low-frequency alterations, captures recurrent mutations, copy number alterations (CNAs) and structural variants (SVs) and characterizes coordinate genetic signatures in 304 primary DLBCLs with available outcome data. We integrated these genetic drivers using consensus clustering and identified 5 robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; 2 distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss and associated genomic instability. The genetic features of the newly identified subsets, their mutational signatures and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, these studies provide a roadmap for an actionable DLBCL classification. </p>
Project description:microRNAs er are group of short noncoding RNAs that regulate gene expression at the posttranslational level. It has been shown that mirs are independent predictios of outcome in patients with diffuse large b cell lymphoma treated with r-chop. Outcome in patients with dlbcl lymphoma treated with r-chop. Based on the measured GI50 in 60 human cell lines. 116 DLBCL samples
Project description:microRNAs er are group of short noncoding RNAs that regulate gene expression at the posttranslational level. It has been shown that mirs are independent predictios of outcome in patients with diffuse large b cell lymphoma treated with r-chop. Outcome in patients with dlbcl lymphoma treated with r-chop. Based on the measured GI50 in 60 human cell lines.
Project description:The distinction between the Burkitt lymphoma and diffuse large B-cell lymphoma is imprecise using current diagnostic criteria. We applied transcriptional and genomic profiling to molecularly define Burkitt lymphoma. Gene expression profiling employing Affymetrix GeneChips (U133A) was performed in 220 mature aggressive B-cell lymphomas, including a core group of eight Burkitt lymphomas, which fulfilled all diagnostic criteria of the WHO classification. A molecular signature of Burkitt lymphoma was generated. Chromosomal abnormalities were detected by interphase fluorescence in-situ hybridization and array comparative genomic hybridization. The molecular Burkitt lymphoma signature identified 44 cases. Fifteen of these cases lacked a morphology typical for Burkitt/Burkitt-like lymphoma. The vast majority (88%) of the 176 lymphomas without the molecular Burkitt lymphoma signature represented diffuse large B-cell lymphomas. In 20% of these cases a MYC break was detectable which was associated with complex chromosomal changes. Our molecular definition of Burkitt lymphoma sharpens and extends the spectrum of Burkitt lymphoma. In mature aggressive B-cell lymphomas without a Burkitt lymphoma signature, a chromosomal break in the MYC locus proved to be associated with adverse clinical outcome. Experiment Overall Design: 220 diffuse large B-cell lymphoma and Burkitt lymphoma samples hybridized to 221 HGU133A Affymetrix GeneChips
Project description:Large cell lymphomas of the gastrointestinal tract are currently regarded as diffuse large B-cell lymphomas despite a more favourable clinical outcome and a lower aggressiveness compared to other nodal and extranodal DLBCL. We compared gene expression profiles of 28 gastrointestinal marginal zone B-cell lymphomas and variants with several other B-cell lymphoma entities such as Burkitt’s lymphoma, nodal DLBCL, follicular lymphoma, mantle cell lymphoma, primary mediastinal B-cell lymphoma and normal B-cell populations. Based on a subset of NF-kappaB target genes, partitioning and hierarchical cluster algorithms were used which led to comparable results. The different B-cell subsets, the Burkitt’s lymphoma, and the small cell lymphomas formed distinct groups, respectively. The DLBCL were subdivided into one group containing only DLBCL samples, one subset clustered together with the PMBL samples, and another one together with the blastic variants of MZBL. These results implicate that extranodal blastic MZBL represent a distinct subgroup of DLBCL.
Project description:A better understanding of the pathogenesis of diffuse large B-cell lymphoma (DLBCL) has clarified its relationship to normal B-cells, pointed to distinct mechanisms of cell transformation, and facilitated the design of novel treatments. However, these data derive from mRNA genes studies, whereas genome-wide integrative investigations of the role of microRNAs (miRNAs) in DLBCL are still unavailable. We used array-CGH and microarray-based expression analyses to map the abnormalities targeting miRNAs in DLBCLs (n=86). Using training and validation DLBCL cohorts, we defined a collection of miRNAs that robustly segregates these tumors in three unique subsets. This miRNA-driven substructure appears to influence disease outcome, is independent of other mRNA-based DLBCL classifications, and stems from copy number changes targeting the miRNA genome, MYC activity, and the miRNA fingerprints of mature normal B-cells. Our data have uncovered clinically relevant additional molecular complexity in DLBCL and have established a blueprint for the detailed characterizations of miRNAs that are pertinent to B-cell lymphoma biology.