# Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes

Source: https://onco.cc/key-papers/paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018/  
OnCo record `paper-chapuy-molecular-subtypes-dlbcl-nat-med-2018` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Reading the whole genetic picture of 304 lymphomas, rather than one gene at a time, sorted them into five groups that arise by different routes and respond differently.

## Summary

Chapuy, Shipp and colleagues carried out a comprehensive genetic analysis of 304 primary diffuse large B-cell lymphomas, capturing recurrent mutations, somatic copy-number alterations, structural variants and low-frequency changes together rather than separately, and then clustered the combined signatures.

Five robust subsets came out. One was a previously unrecognised group of low-risk activated B-cell tumours of extrafollicular or marginal zone origin. Two were distinct germinal-centre groups with different outcomes and different targetable alterations. One was independent of the activated and germinal-centre division altogether, defined by biallelic inactivation of TP53, loss of CDKN2A and the genomic instability that follows. The coordinate genetic signatures predicted outcome independently of the clinical International Prognostic Index.

The paper was published three weeks after Schmitz's from the National Cancer Institute, which used a different algorithm on a different cohort and produced four subtypes rather than five. That the two classifications overlap but do not coincide is the central problem the field then had to solve, and Wright's probabilistic tool in 2020 was the attempt to solve it.

## Fields

- Kind: Key paper
- Last checked: 2026-10-01
- Also known as: Chapuy 2018; Five genetic clusters of diffuse large B-cell lymphoma; C1 to C5 clusters
- Tags: lymphoma-evidence
- Journal: Nature Medicine
- Year: 2018
- DOI: 10.1038/s41591-018-0016-8
- Authors: Chapuy B, Stewart C, Dunford AJ, et al.
- Findings: Consensus clustering of integrated mutations, copy-number alterations and structural variants in 304 primary diffuse large B-cell lymphomas identified five robust genetic subsets.; One subset was a previously unrecognised group of low-risk activated B-cell tumours of extrafollicular or marginal zone origin.; Two distinct germinal-centre subsets differed in outcome and in targetable alterations.; One subset was independent of the activated and germinal-centre division and was defined by biallelic TP53 inactivation, CDKN2A loss and associated genomic instability.; The coordinate genetic signatures predicted outcome independently of the clinical International Prognostic Index.
- What it means: One of the two foundational genetic classifications of diffuse large B-cell lymphoma. Neither has yet changed what a patient receives outside a trial, but together they are the reason precision-medicine trials in this disease now select by genetics rather than by cell of origin.
- Caveats: Five clusters from 304 tumours is a discovery result; cluster boundaries move with cohort and method, which is exactly what the comparison with Schmitz showed.; The clusters were derived and their prognostic value assessed in largely the same cohort.; No prospective trial has yet assigned treatment by these clusters, so their therapeutic implications remain hypotheses.; The publisher issued a correction and an author correction to this paper in 2018; both are indexed separately on Europe PMC.

## Sources

- Nature Medicine 2018: https://doi.org/10.1038/s41591-018-0016-8
- PubMed: https://pubmed.ncbi.nlm.nih.gov/29713087/
- Europe PMC: https://europepmc.org/article/MED/29713087

## 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/), [Genetics and pathogenesis of diffuse large B-cell lymphoma](https://onco.cc/key-papers/paper-schmitz-genetics-pathogenesis-dlbcl-nejm-2018/)
- 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/)
- 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/), [International Prognostic Index (IPI)](https://onco.cc/terms/ipi-score/), [Next-generation sequencing (NGS)](https://onco.cc/terms/ngs/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/)
- 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/), [MYD88](https://onco.cc/targets/myd88/), [NOTCH2](https://onco.cc/targets/notch2/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/)
- bottlenecks: [Biomarkers are not validated or standardised](https://onco.cc/bottlenecks/b-biomarker-validation/), [The valley of death between lab and product](https://onco.cc/bottlenecks/b-translational-valley/), [Tumour heterogeneity and clonal evolution](https://onco.cc/bottlenecks/b-tumor-heterogeneity/)
- journals: [Nature Medicine](https://onco.cc/journals/nature-medicine/)
- 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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