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Sequencing 574 lymphomas found four genetic patterns that recur, two of which depend on a signalling route that an existing tablet can block.
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.
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.
The piece that turns a research classification into something a trial can use on one person's biopsy, with a probability attached rather than a flat label. It is the reason genetics-directed lymphoma trials became possible at all.
A failure worth reading: the drug worked where patients could tolerate the regimen it was added to, and harmed where they could not. It is the strongest argument in lymphoma for designing first-line combinations around what an older patient can finish.
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.
The reason a pathology report on diffuse large B-cell lymphoma says germinal-centre or non-germinal-centre, and the origin of every attempt since to treat the two differently. It also made the case that microarray profiling could do something the clinical index could not, which is what pulled genomics into haematology.
Shares The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma, BCL6, Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX), A probabilistic classification tool for genetic subtypes of diffuse large B cell lymphoma with therapeutic implications and the tag lymphoma-evidence.
Shares Cell of origin (GCB vs ABC), Next-generation sequencing (NGS), Whole-exome & whole-genome sequencing, Biomarkers are not validated or standardised and the tag lymphoma-evidence.
Shares ARCHED, CD79b, 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, Diffuse large B-cell lymphoma and the tag lymphoma-evidence.
Shares Next-generation sequencing (NGS), Biomarkers are not validated or standardised, Trial design, endpoints and cost, 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 and the tag lymphoma-evidence.
Shares Cell of origin (GCB vs ABC), Biomarkers are not validated or standardised, 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, Diffuse large B-cell lymphoma and the tag lymphoma-evidence.
Shares Cell of origin (GCB vs ABC), Biomarkers are not validated or standardised, 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, Diffuse large B-cell lymphoma and the tag lymphoma-evidence.
Shares B-cell receptor / BTK signalling (to NF-κB), BTK (Bruton tyrosine kinase), 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, New England Journal of Medicine and the tag lymphoma-evidence.
Shares B-cell receptor / BTK signalling (to NF-κB), BTK (Bruton tyrosine kinase), 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, Non-Hodgkin lymphoma (all types) and the tag lymphoma-evidence.