# LymphGen and the genetic clusters of large B-cell lymphoma

Source: https://onco.cc/terms/lymphoma-bio-lymphgen/  
OnCo record `lymphoma-bio-lymphgen` (Term). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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).

LymphGen 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).

The 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.

## Fields

- Kind: Term
- Last checked: 2026-09-30
- Also known as: LymphGen; MCD subtype; BN2 subtype; EZB subtype; N1 subtype; DLBCL genetic subtypes; Chapuy clusters

## Sources

- Schmitz et al., N Engl J Med 2018: genetics and pathogenesis of diffuse large B-cell lymphoma (574 biopsies; MCD, BN2, N1, EZB): https://doi.org/10.1056/NEJMoa1801445
- Chapuy et al., Nat Med 2018: five genetic subsets of diffuse large B-cell lymphoma from 304 primary tumours: https://doi.org/10.1038/s41591-018-0016-8
- Wright et al., Cancer Cell 2020: LymphGen, a probabilistic classifier for seven genetic subtypes: https://doi.org/10.1016/j.ccell.2020.03.015

## Connected records

- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Marginal zone lymphoma](https://onco.cc/cancers/marginal-zone-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BCL6](https://onco.cc/targets/bcl6/), [CD79b](https://onco.cc/targets/cd79b/), [CDKN2A](https://onco.cc/targets/cdkn2a/), [EZH2](https://onco.cc/targets/ezh2/), [MYD88](https://onco.cc/targets/myd88/), [NOTCH1](https://onco.cc/targets/notch1/), [NOTCH2](https://onco.cc/targets/notch2/), [TP53](https://onco.cc/targets/tp53/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/)
- terms: [Cell of origin (GCB vs ABC)](https://onco.cc/terms/cell-of-origin/), [Cell of origin in practice: Hans against expression profiling, and what it changes](https://onco.cc/terms/lymphoma-bio-cell-of-origin-in-practice/), [MYD88 L265P and CXCR4 mutations](https://onco.cc/terms/myd88-l265p/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- biomarkers: [CD79B ITAM mutation](https://onco.cc/biomarkers/cd79b-itam-mutation/), [EZH2 gain-of-function mutation (Tyr646, originally Tyr641)](https://onco.cc/biomarkers/ezh2-y646-mutation/)

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