Whole-exome analysis reveals novel somatic genomic alterations associated with cell of origin in diffuse large B-cell lymphoma

Manso, Bryce; Wenzl, Kerstin; Asmann, Yan W.; Maurer, Matthew J.; Manske, Michelle K.; Yang, Zhi Zhang; Slager, Susan L.; Nowakowski, Grzegorz S.; Ansell, Stephen M.; Witzig, Thomas E.; Feldman, Andrew L.; Rimsza, Lisa M.; Link, Brian K.; Cerhan, James R.; Novak, Anne J.

doi:10.1038/bcj.2017.33

Cited by 9 publications

(5 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PMBCL also differs from ABC and GCB subtypes of DLBCL in somatic mutation profiles. ABC DLBCLs frequently have mutations in MYD88 , CD79B , and CARD11 , while GCB DLBCLs often have mutations in CREBBP , EZH2 , TNFRSF14 , and BCL2 13,44 . On the other hand, genes frequently mutated in PMBCL include STAT6 , TNFAIP3 , SOCS1 , CD58 , and CIITA 44 .…”

Section: Resultsmentioning

confidence: 99%

Amplification of 9p24.1 in diffuse large B-cell lymphoma identifies a unique subset of cases that resemble primary mediastinal large B-cell lymphoma

et al. 2019

View full text Add to dashboard Cite

Copy number alterations (CNAs) of 9p24.1 occur frequently in Hodgkin lymphoma, primary mediastinal large B-cell lymphoma (PMBCL), primary central nervous system lymphoma, and primary testicular lymphoma, resulting in overexpression of PD-L1 and sensitivity to PD-1 blockade-based immunotherapy. While 9p24.1 CNA was also reported in diffuse large B-cell lymphoma (DLBCL), little is known about its molecular or clinical significance. In this study, we analyzed the prevalence of 9p24.1 CNA in newly diagnosed DLBCL and examined its association with PD-L1, PD-L2, and JAK2 expression, clinical characteristics, and outcome. We found that 10% of DLBCL cases had CNA of 9p24.1, with 6.5% gains, and 3.5% amplifications. Only the cases with a 9p24.1 amplification had high levels of PD-L1, PD-L2, and JAK2 expression. Gains or amplifications of 9p24.1 were associated with a younger age and the ABC/non-GCB subtype. Compared with DLBCL cases without 9p24.1 CNA, the cases with a 9p24.1 amplification had a trend of better event-free survival. Furthermore, the amplification cases had a gene expression and mutation profile similar to those of PMBCL. Our data suggest that amplification of 9p24.1 identifies a unique subset of DLBCL with clinical and molecular features resembling PMBCL that may be amenable to PD-1 blockade-based immunotherapy.

show abstract

Section: Resultsmentioning

confidence: 99%

Amplification of 9p24.1 in diffuse large B-cell lymphoma identifies a unique subset of cases that resemble primary mediastinal large B-cell lymphoma

et al. 2019

View full text Add to dashboard Cite

show abstract

“…It was considered a subtype of diffuse large B-cell lymphoma (DLBCL) but, due to distinct clinicopathological features, it was acknowledged as a discrete entity in the 2008 World Health Organization (WHO) diagnostic criteria (Campo et al, 2011). This distinction from other DLBCL subtypes has been confirmed at a molecular level using gene expression profiling (Rosenwald et al, 2003;Manso et al, 2017). In fact, PMBCL is more akin to nodular sclerosing Hodgkin lymphoma (NScHL) than DLBCL.…”

mentioning

confidence: 86%

Biology and therapy of primary mediastinal B‐cell lymphoma: current status and future directions

et al. 2019

View full text Add to dashboard Cite

Summary Primary mediastinal B‐cell lymphoma ( PMBCL ) is a distinct disease closely related to classical nodular sclerosing Hodgkin lymphoma. Conventional diagnostic paradigms utilising clinical, morphological and immunophenotypical features can be challenging due to overlapping features with other B‐cell lymphomas. Reliable diagnostic and prognostic biomarkers that are applicable to the conventional diagnostic laboratory are largely lacking. Nuclear factor kappa B ( NF ‐κB) and Janus kinase/signal transducers and activators of transcription ( JAK ‐ STAT ) signalling pathways are characteristically dysregulated in PMBCL and implicated in several aspects of disease pathogenesis, and the latter pathway in host immune evasion. The tumour microenvironment is manipulated by PMBCL tumours to avoid T‐cell mediated destruction via strategies that include loss of tumour cell antigenicity, T‐cell exhaustion and activation of suppressive T‐regulatory cells. R‐ CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) and DA ‐ EPOCH ‐R (dose‐adjusted etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, rituximab) are the most common first‐line immunochemotherapy regimens. End of treatment positron emission tomography scans are the recommended imaging modality and are being evaluated to stratify patients for radiotherapy. Relapsed/refractory disease has a relatively poor outcome despite salvage immunochemotherapy and subsequent autologous stem cell transplantation. Novel therapies are therefore being developed for treatment‐resistant disease, targeting aberrant cellular signalling and immune evasion.

show abstract

“…The tumor necrosis factor (TNF) receptor superfamily member HVEM (encoded by the gene TNFRSF14 ) is the most highly mutated surface molecule in GC-derived follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) (Cheung et al., 2010, Lackraj et al., 2018, Launay et al., 2012, Manso et al., 2017, Schmitz et al., 2018). HVEM is expressed in B cells as well as several other cell types and has multiple ligands.…”

Section: Introductionmentioning

confidence: 99%

The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

et al. 2019

View full text Add to dashboard Cite

Summary The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.

show abstract

Whole-exome analysis reveals novel somatic genomic alterations associated with cell of origin in diffuse large B-cell lymphoma

Cited by 9 publications

References 17 publications

Amplification of 9p24.1 in diffuse large B-cell lymphoma identifies a unique subset of cases that resemble primary mediastinal large B-cell lymphoma

Amplification of 9p24.1 in diffuse large B-cell lymphoma identifies a unique subset of cases that resemble primary mediastinal large B-cell lymphoma

Biology and therapy of primary mediastinal B‐cell lymphoma: current status and future directions

The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

Contact Info

Product

Resources

About