# Genetics and pathogenesis of diffuse large B-cell lymphoma

Source: https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/  
OnCo record `paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Sequencing 574 lymphomas found four genetic patterns that recur, two of which depend on a signalling route that an existing tablet can block.

## Summary

Schmitz, Staudt and colleagues studied 574 diffuse large B-cell lymphoma biopsy samples by exome and transcriptome sequencing, array copy-number analysis and targeted resequencing of 372 genes, and built an algorithm that discovers subtypes from the co-occurrence of genetic alterations rather than from expression alone.

Four genetic subtypes emerged, each named for the alterations that define it: MCD, for co-occurring MYD88 L265P and CD79B mutations; BN2, for BCL6 fusions and NOTCH2 mutations; N1, for NOTCH1 mutations; and EZB, for EZH2 mutations and BCL2 translocations. They differed in gene-expression signature and in response to immunochemotherapy, with favourable survival in BN2 and EZB and inferior outcomes in MCD and N1.

The therapeutic reading is the point of the paper. MCD and BN2 tumours appear to depend on chronic active B-cell receptor signalling, which Bruton tyrosine kinase inhibitors block. That is the mechanistic argument behind the small group of patients in whom ibrutinib added to R-CHOP produced long remissions in the otherwise negative PHOENIX trial, and behind the current generation of genetics-directed trials.

## Fields

- Kind: Key paper
- Last checked: 2026-10-01
- Also known as: Schmitz 2018; MCD, BN2, N1 and EZB subtypes; National Cancer Institute genetic subtypes
- Tags: lymphoma-evidence
- Journal: New England Journal of Medicine
- Year: 2018
- DOI: 10.1056/NEJMoa1801445
- Authors: Schmitz R, Wright GW, Huang DW, et al.
- Findings: Four genetic subtypes of diffuse large B-cell lymphoma were identified from 574 biopsy samples: MCD (MYD88 L265P with CD79B mutations), BN2 (BCL6 fusions with NOTCH2 mutations), N1 (NOTCH1 mutations) and EZB (EZH2 mutations with BCL2 translocations).; The subtypes differed in gene-expression signature and in response to immunochemotherapy.; Survival was favourable in the BN2 and EZB subtypes and inferior in MCD and N1.; Pathway analysis suggested that MCD and BN2 lymphomas rely on chronic active B-cell receptor signalling, which is amenable to therapeutic inhibition.
- What it means: The genetic nosology that precision-medicine trials in diffuse large B-cell lymphoma now use to pick patients. It gives a mechanism, not just a label: two of the four subtypes point at a drug class that already exists.
- Caveats: Published within weeks of Chapuy's five-cluster classification from a different cohort using a different algorithm; the two agree in part and disagree in part, and reconciling them took two further years.; A substantial minority of tumours fit none of the four subtypes and are left unclassified.; Outcome differences come from retrospective cohorts treated with R-CHOP, not from a trial that assigned treatment by subtype.; The B-cell receptor dependency is inferred from pathway analysis and cell-line models rather than demonstrated in patients by this paper.

## Sources

- New England Journal of Medicine 2018: https://doi.org/10.1056/NEJMoa1801445
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29641966/
- Europe PMC: https://europepmc.org/article/MED/29641966

## Connected records

- key papers: [A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications](https://onco.cc/key-papers/paper-wright-lymphgen-genetic-subtypes-dlbcl-cancer-cell-2020/), [Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes](https://onco.cc/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/), [Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)](https://onco.cc/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/), [The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma](https://onco.cc/key-papers/paper-rosenwald-molecular-profiling-dlbcl-nejm-2002/)
- roadmaps: [Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting](https://onco.cc/roadmaps/lymphoma-roadmap/)
- cancers: [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/)
- fronts: [Diagnostics & Biomarkers](https://onco.cc/fronts/diagnostics/), [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [Whole-exome & whole-genome sequencing](https://onco.cc/technologies/wes-wgs/)
- terms: [Cell of origin (GCB vs ABC)](https://onco.cc/terms/cell-of-origin/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BCL6](https://onco.cc/targets/bcl6/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CD79b](https://onco.cc/targets/cd79b/), [EZH2](https://onco.cc/targets/ezh2/), [MYD88](https://onco.cc/targets/myd88/), [NOTCH1](https://onco.cc/targets/notch1/), [NOTCH2](https://onco.cc/targets/notch2/)
- institutions: [National Cancer Institute (NIH)](https://onco.cc/institutions/nci/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/)
- trials: [ARCHED](https://onco.cc/trials/arched/), [PHOENIX DDR/Anti-PD-L1](https://onco.cc/trials/phoenix/)
- people: [Louis M. Staudt](https://onco.cc/people/louis-staudt/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)
- ideas: [Assign first-line treatment in diffuse large B-cell lymphoma by genetic subtype, not by a three-antibody stain](https://onco.cc/ideas/lymphoma-ev-genetic-subtype-directed-first-line/)

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