Towards genomic-based prognostication and precision therapy for diffuse large B-cell lymphoma

Minderman, Marthe; Pals, Steven T.

doi:10.3324/haematol.2020.255448

Cited by 2 publications

(3 citation statements)

References 24 publications

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“…Genetic classification based on multiple analytic platforms, including mutations, translocations, and/or copy-number alterations, divides DLBCL into distinct clusters with discrete genetic signatures and different clinical characteristics ( 24 ). Chapuyg et al ( 25 ) discovered six robust subsets (C0–C5) by applying non-negative matrix factorization consensus.…”

Section: Discussionmentioning

confidence: 99%

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Chai

Chen

et al. 2021

Front. Oncol.

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Primary gastrointestinal diffuse large B-cell lymphoma (GI-DLBCL) is the most common gastrointestinal lymphoma, but its genetic features are poorly understood. We performed whole-exome sequencing of 25 primary tumor samples from patients with GI-DLBCL and 23 matched normal tissue samples. Oncogenic mutations were screened, and the correlations between genetic mutations and clinicopathological characteristics were analyzed. Twenty-five patients with GI-DLBCL were enrolled in the genetic mutation analysis with a median of 184 (range 79–382) protein-altering variants per patient. We identified recurrent oncogenic mutations in GI-DLBCL, including those in TP53, MUC16, B2M, CCND3, HIST1H1C, NEB, and ID3. Compared with nodal DLBCL, GI-DLBCL exhibited an increased mutation frequency of TP53 and reduced mutation frequencies of PIM1, CREBBP, BCL2, KMT2D, and EZH2. Moreover, GI-DLBCL exhibited fewer MYD88 and CD79B mutations than DLBCL in the testis and central nervous system. GI-DLBCLs with HLA-B, MEF2A, RHOA, and NAV3 mutations exhibited a tendency toward a high proliferation index. MUC16 and ETV6 mutations often occurred in tumors with early clinical staging. Our data provide a comprehensive understanding of the landscape of mutations in a small subset of GI-DLBCLs. The genetic mutation profiles of GI-DLBCL differ from those of nodal DLBCL and DLBCL in immune-privileged sites. The different mutated genes are related to the NF-κB and JAK-STAT pathways, and the different pathogenetic mechanisms leading to the development of DLBCL may be influenced by the tissue microenvironment. Differences in genetic alterations might influence the clinicopathological characteristics of GI-DLBCL.

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Section: Discussionmentioning

confidence: 99%

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Chai

Chen

et al. 2021

Front. Oncol.

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“…ABC-like DLBCL present a highly active NF-κB pathway like differentiating cells, which cannot reach the plasma or memory cell fate. Here, the most prominent altered genes are CARD11 , MYD88, TNFAIP3 , and CD79B [ 13 ]. Especially DLBCLs of type ABC show less responsiveness upon standard treatment and are therefore the focus of further studies [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…Especially DLBCLs of type ABC show less responsiveness upon standard treatment and are therefore the focus of further studies [ 14 ]. However, there are also patients with a GCB-like profile with an unfavorable outcome, suggesting that transcriptional signatures only partially capture the features relevant for outcome prediction [ 13 ]. More recently, comprehensive sequencing studies of DLBCL facilitated a more refined subclassification of the heterogeneous genomic profiles of DLBCL patients [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Patient-Specific Modeling of Diffuse Large B-Cell Lymphoma

et al. 2021

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Personalized medicine aims to tailor treatment to patients based on their individual genetic or molecular background. Especially in diseases with a large molecular heterogeneity, such as diffuse large B-cell lymphoma (DLBCL), personalized medicine has the potential to improve outcome and/or to reduce resistance towards treatment. However, integration of patient-specific information into a computational model is challenging and has not been achieved for DLBCL. Here, we developed a computational model describing signaling pathways and expression of critical germinal center markers. The model integrates the regulatory mechanism of the signaling and gene expression network and covers more than 50 components, many carrying genetic lesions common in DLBCL. Using clinical and genomic data of 164 primary DLBCL patients, we implemented mutations, structural variants and copy number alterations as perturbations in the model using the CoLoMoTo notebook. Leveraging patient-specific genotypes and simulation of the expression of marker genes in specific germinal center conditions allows us to predict the consequence of the modeled pathways for each patient. Finally, besides modeling how genetic perturbations alter physiological signaling, we also predicted for each patient model the effect of rational inhibitors, such as Ibrutinib, that are currently discussed as possible DLBCL treatments, showing patient-dependent variations in effectiveness and synergies.

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Towards genomic-based prognostication and precision therapy for diffuse large B-cell lymphoma

Cited by 2 publications

References 24 publications

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Genomic Mutation Profile of Primary Gastrointestinal Diffuse Large B-Cell Lymphoma

Patient-Specific Modeling of Diffuse Large B-Cell Lymphoma

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