Table of Contents

Overview

CD79B mutations significantly contribute to the pathogenesis of DLBCL by enhancing BCR signaling and promoting tumor survival. These mutations, especially when co-occurring with MYD88 mutations, define a unique molecular subtype.1 This has clinical and therapeutic implications as it may contribute sensitivity to BTK inhibitors. In an inducible mouse model of MYD88-driven DLBCL, CD79B mutations did not accelerate lymphomagenesis but demonstrated an increased sensitivity to pharmacological BTK inhibition.2 In a retrospective analysis, younger patients with MCD DLBCL that were treated with ibrutinib had significantly better outcomes.3 The most common hotspot mutation in CD79B is at the tyrosine residue 196 (Y196). This and other common mutations primarily occur in the immunoreceptor tyrosine-based activation motif (ITAM) domain and prevent the negative regulatory feedback provided by Lyn kinase thereby enhancing BCR signaling.4,5

Experimental Evidence

Driver mutations affecting this gene in DLBCL have been experimentally demonstrated to cause a gain of function (GOF).5

Clinical Relevance

CD79B is both a recurrent oncogenic signalling node in ABC-DLBCL and an ideal lineage-restricted, rapidly internalizing surface antigen. The antibody–drug conjugate polatuzumab vedotin exploits CD79B surface expression to deliver a cytotoxic payload to malignant B cells, independent of CD79B mutation status6. Polatuzumab vedotin has FDA approval for use in combination with bendamustine and a rituximab product for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, after at least two prior therapies. More recently, it was FDA approved for use with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS), or high-grade B-cell lymphoma (HGBL) and who have an International Prognostic Index (IPI) score of 2 or greater.

Relevance tier by entity

Entity Tier Description
BL 3 Mutations are unlikely to be relevant to BL
DLBCL 1 High-confidence DLBCL gene
FL 2 Role of CD79B mutations in FL requires confirmation

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

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FL

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Mutation pattern and selective pressure estimates

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CD79B Hotspots

Mutations at Y196 enhance B-cell receptor (BCR) signaling by preventing the negative regulatory feedback provided by Lyn kinase, a feedback inhibitor of BCR signaling. This results in continuous activation of the NF-κB pathway, promoting tumor cell survival and proliferation.4

Chromosome Coordinate (hg19) ref>alt HGVSp
chr17 62007234 C>G A150P
chr17 62007234 C>T A150T
chr17 62007233 G>A A150V
chr17 62007140 A>G L181P
chr17 62007129 C>T X184_splice
chr17 62006798 T>A Y197F
chr17 62006798 T>C Y197C
chr17 62006799 A>C Y197D
chr17 62006799 A>G Y197H
chr17 62006798 T>G Y197S
chr17 62006795 T>C E198G
chr17 62006680 A>G L200P
chr17 62006680 A>C L200R
chr17 62006680 A>T L200Q
chr17 62006603 G>A H226Y
chr17 62006603 G>T H226N

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Expression

Representative Mutations

BL

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References

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