Targetable activating mutations are very frequent in GCB and ABC diffuse large B‐cell lymphoma

Bohers, Élodie; Mareschal, Sylvain; Bouzelfen, Abdelilah; Marchand, Vinciane; Ruminy, Philippe; Maingonnat, Catherine; Ménard, Anne‐Lise; Étancelin, Pascaline; Bertrand, Philìppe; Dubois, Sydney; Alcantara, Marion; Bastard, Christian; Tilly, Hervé; Jardin, Fabrice

doi:10.1002/gcc.22126

Cited by 81 publications

(56 citation statements)

References 45 publications

(73 reference statements)

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“…Of 17 ABC patients with MYD88 L265P mutations, we found 10 (58.8%) with associated CD79B mutations, who might respond more favorably to Ibrutinib treatment. CD79B mutations were identified in 10.7% of total patients, slightly less than previously reported, but were significantly enriched in ABC DLBCL (24.7%, FDR ¼ 3.2 Â 10 À5 ), corroborating previous studies (13,31). Of note, two (11.8%) MYD88 L265P-mutated ABC patients were CARD11-mutated and two were TNFAIP3-mutated, potentially diminishing the effect of ibrutinib and sotrastaurin, while 6 (35.3%) were PRDM1-mutated ( Supplementary Fig.…”

Section: Lymphopanel Ngs Identifies Mutations With Potential Treatmensupporting

confidence: 89%

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Dubois

Viailly

Mareschal

et al. 2016

Clinical Cancer Research

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Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials.Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20þ de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133þ2.0 Affymetrix GeneChip arrays. Results:The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-celllike (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-kB, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with R-CHOP were associated with significantly less favorable prognoses.Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact.

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Section: Lymphopanel Ngs Identifies Mutations With Potential Treatmensupporting

confidence: 89%

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Dubois

Viailly

Mareschal

et al. 2016

Clinical Cancer Research

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179

155

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“…The identification and characterization of the molecular basis of the dismal prognosis of patients with MYD88-mutant DLBCL could provide the rationale for new treatment targets in the involved pathways. Thus, MYD88 could emerge as a key biomarker in ABC DLBCL (23,25,(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

MYD88L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome

Rovira

Karube

Valera

et al. 2016

Clinical Cancer Research

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Purpose: Mutations in MYD88 are found in different lymphoproliferative disorders associated with particular biologic characteristics and clinical impact. The aim of this study was to analyze the incidence of MYD88 mutations and its clinical impact in diffuse large B-cell lymphoma (DLBCL).Experimental Design: The incidence, clinicobiological features, and outcome of 213 patients (115 M/98 F; median age, 65 years) with DLBCL treated with immunochemotherapy in a single institution according to MYD88 mutational status as assessed by an allele-specific PCR assay were analyzed. The cell of origin (COO) was determined in 129 cases by gene expression.Results: MYD88 mutations were found in 47 cases (22%), including L265P in 39 and S219C and M232F in 4 cases, respectively. Patients with MYD88 L265P were older, presenting frequent extranodal involvement, and mostly corresponded to activated B-cell like (ABC) subtype, whereas no preference in COO was observed in patients with other MYD88 mutations. Five-year overall survival (OS) for MYD88 wildtype, MYD88 L265P, and other variants was 62%, 52%, and 75%, respectively (P ¼ 0.05). International Prognostic Index (IPI) (HR, 2.71; P < 0.001) and MYD88 L265P (HR, 1.786; P ¼ 0.023) were independent variables predicting OS in the multivariate analysis. However, MYD88 L265P lost its independent value when COO was included in the model.Conclusions: Our findings indicate that MYD88 L265P mutations, but no other variants, identify a subgroup of DLBCL mainly of ABC origin, with extranodal involvement and poor outcome.

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“…Mutations affecting two of the latter amino acid residues (P141 and S149) have been previously reported in de novo DLBCL. 45,46 …”

Section: Mutations In Card11 Cd79b and Myd88mentioning

confidence: 99%

Cell of origin of transformed follicular lymphoma

Kridel

Mottok

Farinha

et al. 2015

Blood

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Key Points• TFL is most commonly of the germinal center B-cell-like phenotype, but a significant minority of cases is of the ABC phenotype (16%).• The absence of BCL2 translocation in FL at diagnosis is associated with transformation into ABC-like large cell lymphoma.Follicular lymphoma (FL) is an indolent disease but transforms in 2% to 3% of patients per year into aggressive, large cell lymphoma, a critical event in the course of the disease associated with increased lymphoma-related mortality. Early transformation cannot be accurately predicted at the time of FL diagnosis and the biology of transformed FL (TFL) is poorly understood. Here, we assembled a cohort of 126 diagnostic FL specimens including 40 patients experiencing transformation (<5 years) and 86 patients not experiencing transformation for at least 5 years. In addition, we assembled an overlapping cohort of 155 TFL patients, including 114 cases for which paired samples were available, and assessed temporal changes of routinely available biomarkers, outcome after transformation, as well as molecular subtypes of TFL. We report that the expression of IRF4 is an independent predictor of early transformation (Hazard ratio, 13.3; P < .001). We also show that composite histology at the time of transformation predicts favorable prognosis. Moreover, applying the Lymph2Cx digital gene expression assay for diffuse large B-cell lymphoma (DLBCL) cell-of-origin determination to 110 patients with DLBCL-like TFL, we demonstrate that TFL is of the germinal-center B-cell-like subtype in the majority of cases (80%) but that a significant proportion of cases is of the activated B-cell-like (ABC) subtype (16%). These latter cases are commonly negative for BCL2 translocation and arise preferentially from BCL2 translocation-negative and/or IRF4-expressing FLs. Our study demonstrates the existence of molecular heterogeneity in TFL as well as its relationship to the antecedent FL. (Blood. 2015;126(18):2118-2127

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Targetable activating mutations are very frequent in GCB and ABC diffuse large B‐cell lymphoma

Cited by 81 publications

References 45 publications

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

MYD88L265P Mutations, But No Other Variants, Identify a Subpopulation of DLBCL Patients of Activated B-cell Origin, Extranodal Involvement, and Poor Outcome

Cell of origin of transformed follicular lymphoma

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