Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma

Pedrosa, Lucía; Fernández‐Miranda, Ismael; Pérez-Callejo, David; Quero, Cristina; Rodríguez, Marta; Martín‐Acosta, Paloma; Gómez, Sagrario; González-Rincón, Julia; Santos, Adrián; Tarin, Carlos; Garcı́a, Juan F.; García-Arroyo, Francisco R.; Rueda, Antonio; Camacho, Francisca I.; García‐Cosío, Mónica; Heredero, Ana; Llanos, Marta; Mollejo, Manuela; Piris-Villaespesa, Miguel; Gómez-Codina, José; Yanguas‐Casás, Natalia; Sánchez, Antonio; Piris, Miguel Á.; Provencio, Mariano; Sánchez‐Beato, Margarita

doi:10.1038/s41598-020-80376-0

Cited by 34 publications

(30 citation statements)

References 41 publications

(54 reference statements)

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“…This is important as the lymphoblastoid cell lines are generated from B-cells and points to a non-random accumulation of mutations that are in line with the development of cancer in this cell type. In particular, we identified mutations in key DNA repair genes as well as a statistically significant excess of DNVs in IGLL5 48,49 . This gene is found to be mutated in B-cell lymphomas and protein-coding DNVs are identified in 27 individuals in this cohort; all of which have >100 overall DNVs.…”

Section: Dnvs Identified In Clinically Relevant Variantsmentioning

confidence: 99%

de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project

Ng¹,

Vats

Fritz-Waters³

et al. 2021

Preprint

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Detection of de novo variants (DNVs) is critical for studies of disease-related variation and mutation rates. We developed a GPU-based workflow to call DNVs, using 602 trios from the 1000 Genomes Project as a control. We detected 445,711 DNVs, having a bimodal distribution, with peaks at 200 and 2000 DNVs. The excess DNVs are cell line artifacts that are increasing with cell passage. Reduction in DNVs at CpG sites and in percent of DNVs with a paternal parent-of-origin with increasing number of DNVs supports this finding. Detailed assessment of individual NA12878 across multiple genome datasets from 2012 to 2020 reveals increasing number of DNVs over time. Mutation signature analysis across the set revealed individuals had either 1) age-related, 2) B-cell lymphoma, or 3) no prominent signatures. Our approach provides an important advancement for DNV detection and shows cell line artifacts present in lymphoblastoid cell lines are not always random.

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Section: Dnvs Identified In Clinically Relevant Variantsmentioning

confidence: 99%

de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project

Ng¹,

Vats

Fritz-Waters³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Modified HMRN classification 27 is a complex algorithm and was comparatively in agreement with the LymphGen classification (69%). The two‐step classifier 28 is a simple algorithm and also had good sensitivity and specificity; however, the concordance rate with the LymphGen classification was not satisfactory in all cases (54%). Furthermore, genetically composite cases were not dealt with adequately.…”

Section: Discussionmentioning

confidence: 95%

Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B‐cell lymphoma in a Japanese cohort

et al. 2021

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Summary Recent large‐scale genetic studies have proposed a new genetic classification of diffuse large B‐cell lymphoma (DLBCL), which is clinically and biologically heterogeneous. However, the classification methods were complicated to be introduced into clinical practice. Here we retrospectively evaluated the mutational status and copy number changes of 144 genes in 177 Japanese patients with DLBCL, using targeted DNA sequencing. We developed a simplified algorithm for classifying four genetic subtypes—MYD88, NOTCH2, BCL2, and SGK1—by assessing alterations in 18 representative genes and BCL2 and BCL6 rearrangement status, integrating the significant genes from previous studies. In our cohort and another validation cohort from published data, the classification results in our algorithm showed close agreement with the other established algorithm. A differential prognosis among the four groups was observed. The NOTCH2 group showed a particularly poorer outcome than similar groups in previous reports. Furthermore, our study revealed unreported genetic features in the DLBCL subtypes that are mainly reported in Japanese patients, such as CD5‐positive DLBCL and methotrexate‐associated lymphoproliferative disorders. These results indicate the utility of our simplified method for DLBCL genetic subtype classification, which can facilitate the optimisation of treatment strategies. In addition, our study highlights the genetic features of Japanese patients with DLBCL.

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“…We enrolled 1562 patients with DLBCL treated with R-CHOP regimen, including 837 from George W. Wright et al ( 22 ), 77 from Lucía Pedrosa et al ( 31 ), and 648 from Stuart E. Lacy and colleagues ( 32 ), respectively. Among these patients, 30 (1.92%) cases were identified as NOTCH1 mutations.…”

Section: Resultsmentioning

confidence: 99%

Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma

et al. 2021

Front. Oncol.

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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of large lymphoid B cell malignancy with distinct clinical and genetic features. Recently, NOTCH1 mutations were identified in DLBCL cases by Next-generation sequencing (NGS), but the clinical features and prognostic impact were not systematically studied. Here, NOTCH1 genes in 161 DLBCL samples were sequenced by NGS. The prognostic value of NOTCH1 mutations was assessed in the context of clinical and laboratory factors, such as international prognostic index (IPI), cell-of-origin classification, double expression of BCL2 and c-MYC. The combined data from three Western cohorts were used to validate these results. As a result, NOTCH1 mutations were found in 17(10.6%) patients, and three patients had a hotspot mutation of c.7541_7542delCT. The presence of NOTCH1 mutations was significantly associated with poor complete response and progression free survival(PFS), which was independent of established clinical and laboratory parameters. In addition, 30 (1.92%) of 1562 patients treated with R-CHOP regimen in those combined Western cohorts had NOTCH1 mutations. Meta-analysis of the Western cohorts confirmed that NOTCH1 mutations were also associated with poor PFS and OS. In conclusion, DLBCL patients with the NOTCH1 mutations have worse PFS and OS, and the NOTCH1 mutations can be used as an independent predictor for patients with DLBCL.

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Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma

Cited by 34 publications

References 41 publications

de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project

de novo variant calling identifies cancer mutation profiles in the 1000 Genomes Project

Genetic subtype classification using a simplified algorithm and mutational characteristics of diffuse large B‐cell lymphoma in a Japanese cohort

Clinical Features and Prognostic Significance of NOTCH1 Mutations in Diffuse Large B-Cell Lymphoma

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