{"entity":{"id":"lymphoma-bio-lymphgen","kind":"term","name":"LymphGen and the genetic clusters of large B-cell lymphoma","aka":["LymphGen","MCD subtype","BN2 subtype","EZB subtype","N1 subtype","DLBCL genetic subtypes","Chapuy clusters"],"tldr":"Sequencing shows that large B-cell lymphoma is at least seven diseases, each defined by which faults occur together. The classification explains a great deal about how the disease behaves and currently changes almost nothing about how it is treated.","summary":"Two groups sequenced large series in 2018 and arrived at overlapping answers. Exome and transcriptome sequencing with copy-number analysis across 574 biopsies produced four prominent subtypes named for the lesions that co-occur: MCD for MYD88 L265P with CD79B mutation, BN2 for BCL6 fusions with NOTCH2 mutations, N1 for NOTCH1 mutations, and EZB for EZH2 mutations with BCL2 translocations; survival after immunochemotherapy was better in BN2 and EZB and worse in MCD and N1 (Schmitz 2018). Consensus clustering of 304 primary tumours found five subsets, including a low-risk activated B-cell group of extrafollicular or marginal-zone origin, two germinal-centre subsets with different outcomes, and a group defined by biallelic TP53 inactivation and CDKN2A loss that cuts across cell of origin entirely (Chapuy 2018).\n\nLymphGen is what made these usable on one patient: an algorithm that returns the probability that a lymphoma belongs to one of seven genetic subtypes, and which showed that each subtype shares a pathogenesis with a particular indolent or extranodal lymphoma, so the groups are not statistical artefacts (Wright 2020).\n\nThe limits matter. It needs a sequencing panel that calls mutations, copy number and fusions, not a stain. A substantial share of cases come back unclassified. No regulator licenses anything on a LymphGen call, and no randomised trial has assigned treatment by it. Its real effect so far has been on how trials are designed and how their subgroups are read: the concentration of BTK inhibitor activity in the MCD and N1 subtypes is the clearest example, and it is why the current first-line trials genotype everyone.","asOf":"2026-09-30","links":[{"label":"Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB)","url":"https://doi.org/10.1056/NEJMoa1801445"},{"label":"Chapuy et al., Nat Med 2018: five genetic subsets of diffuse large B-cell lymphoma from 304 primary tumours","url":"https://doi.org/10.1038/s41591-018-0016-8"},{"label":"Wright et al., Cancer Cell 2020: LymphGen, a probabilistic classifier for seven genetic subtypes","url":"https://doi.org/10.1016/j.ccell.2020.03.015"}],"tags":[],"related":[],"cancers":["dlbcl","non-hodgkin-lymphoma","primary-cns-lymphoma"],"sections":[],"technologies":["cgp","wes-wgs"],"targets":["myd88","cd79b","bcl6","notch1","notch2","ezh2","bcl2","tp53","cdkn2a"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-signalling","inflammation-nfkb","germinal-centre-reaction"],"terms":["cell-of-origin","lymphoma-bio-cell-of-origin-in-practice","ngs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"category":"Diagnostics & imaging"},"route":"/terms/lymphoma-bio-lymphgen/","neighbours":{"cancer":[{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"marginal-zone-lymphoma","kind":"cancer","name":"Marginal zone lymphoma","route":"/cancers/marginal-zone-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","route":"/cancers/primary-cns-lymphoma/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"bcl6","kind":"target","name":"BCL6","route":"/targets/bcl6/"},{"id":"cd79b","kind":"target","name":"CD79b","route":"/targets/cd79b/"},{"id":"cdkn2a","kind":"target","name":"CDKN2A","route":"/targets/cdkn2a/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"myd88","kind":"target","name":"MYD88","route":"/targets/myd88/"},{"id":"notch1","kind":"target","name":"NOTCH1","route":"/targets/notch1/"},{"id":"notch2","kind":"target","name":"NOTCH2","route":"/targets/notch2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"}],"term":[{"id":"cell-of-origin","kind":"term","name":"Cell of origin (GCB vs ABC)","route":"/terms/cell-of-origin/"},{"id":"lymphoma-bio-cell-of-origin-in-practice","kind":"term","name":"Cell of origin in practice: Hans against expression profiling, and what it changes","route":"/terms/lymphoma-bio-cell-of-origin-in-practice/"},{"id":"myd88-l265p","kind":"term","name":"MYD88 L265P and CXCR4 mutations","route":"/terms/myd88-l265p/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"biomarker":[{"id":"cd79b-itam-mutation","kind":"biomarker","name":"CD79B ITAM mutation","route":"/biomarkers/cd79b-itam-mutation/"},{"id":"ezh2-y646-mutation","kind":"biomarker","name":"EZH2 gain-of-function mutation (Tyr646, originally Tyr641)","route":"/biomarkers/ezh2-y646-mutation/"}]}}