Table of Contents

Overview

BTG1 is one of a number of genes affected by aberrant somatic hypermutation in B-cell lymphomas, which complicates the interpretation of mutations at this locus. These mutations are a feature of the MCD genetic subgroup of DLBCL.

Experimental Evidence

Mutations in the BTG1 gene have been implicated in the pathogenesis and progression of diffuse large B-cell lymphoma (DLBCL) through functional exploration in vivo. Knock-out of BTG1 did not lead to spontaneous lymphomagenesis but enhanced the lymphoproliferation induced by VavP-BCL2 and promoted lymphoma dissemination in xenotransplantation experiments.1 Another study demonstrated that specific BTG1 mutations afford germinal center (GC) B cells with a fitness advantage relative to un-mutated counterparts.2

Relevance tier by entity

Entity Tier Description
BL 2 Role of BTG1 mutations in BL requires confirmation
DLBCL 1 High-confidence DLBCL gene
FL 2 Role of BTG1 mutations in FL requires confirmation
MZL 1 High-confidence MZL gene
PMBL 1 High-confidence PMBL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 137 0.1258 [0.1061,0.1455]
DLBCL GAMBL with Reddy 2,088 212 0.1015 [0.0886,0.1145]
DLBCL BC 231 21 0.0909 [0.0538,0.128]
DLBCL Dana-Farber 303 43 0.1419 [0.1026,0.1812]
DLBCL NCI 470 68 0.1447 [0.1129,0.1765]
DLBCL Reddy 999 75 0.0751 [0.0587,0.0914]
DLBCL DLBCL_ICGC 85 5 0.0588 [0.0088,0.1088]

FL

pathology Collection N mutated Incidence CI
FL GAMBL without Crouch 642 39 0.0607 [0.0423,0.0792]
FL GAMBL with Crouch 1,189 80 0.0673 [0.053,0.0815]
FL BC 379 19 0.0501 [0.0282,0.0721]
FL Kalmbach 164 14 0.0854 [0.0426,0.1281]
FL Crouch 547 41 0.0750 [0.0529,0.097]
FL FL_ICGC 99 6 0.0606 [0.0136,0.1076]

BL

pathology Collection N mutated Incidence CI
BL GAMBL without ICGC/Zhou 320 3 0.0007 [0,0.0035]
BL GAMBL with Panea 410 3 0.0007 [0,0.0033]
BL BLGSP 219 0 0.0005 [0,0.0033]
BL Zhou/ICGC 90 0 0.0011 [0,0.008]
BL Panea 101 3 0.0297 [0,0.0628]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 0.0000 0.0000 1.0000
FL 2.1621 5.0645 0.0233
DLBCL 0.3852 0.7149 0.0000

aSHM regions

chr_name hg19_start hg19_end region regulatory_comment
chr12 92537999 92539598 TSS active_promoter

BTG1 Hotspots

Q36H Conditional knock-in mouse models expressing the BTG1 Q36H mutation in B cells have shown that these mutations lead to earlier onset of lymphoma, shorter survival, and dysplastic B cell infiltration into non-lymphoid organs. These findings reinforce the role of BTG1 mutations in enhancing lymphoma aggressiveness.3

L26P, G66D, and I115V Have each been shown to be unable to rescue wild-type BTG1 activity in a xenotransplantation model, suggesting that they impair BTG1 function.2

Chromosome Coordinate (hg19) ref>alt HGVSp
chr12 92539221 G>A L31F
chr12 92539209 G>A R35*
chr12 92539204 C>G Q36H
chr12 92539203 G>T L37M
chr12 92539203 G>C L37V
chr12 92539198 C>A Q38H
chr12 92539195 GG>CA T39M
chr12 92539190 C>T S41N
chr12 92539189 G>C S41R
chr12 92539184 C>T S43N
chr12 92539179 G>A Q45*
chr12 92539174 C>G E46D
chr12 92539173 G>C L47V
chr12 92539167 C>T A49T
chr12 92539164 C>T E50K
chr12 92539164 C>G E50Q
chr12 92538218 A>C Y52D
chr12 92538217 T>C Y52C
chr12 92538215 T>C K53E

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Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2011-07-27 : Morin : DLBCL 2012-03-06 : Lohr : DLBCL 2013-01-01 : Zhang : DLBCL 2013-08-15 : Morin : DLBCL 2017-10-10 : Reddy : DLBCL 2018-04-12 : Schmitz : DLBCL 2018-05-01 : Chapuy : DLBCL 2021-04-01 : Sarkozy : PMBL 2022-07-06 : Burkhardt : BL

References

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Mlynarczyk C, Teater M, Pae J, Chin CR, Wang L, Arulraj T, Barisic D, Papin A, Hoehn KB, Kots E, Ersching J, Bandyopadhyay A, Barin E, Poh HX, Evans CM, Chadburn A, Chen Z, Shen H, Isles H, Pelzer BW, Tsialta I, Doane A, Geng H, Rehman MH, Melnick J, Morgan W, Nguyen D, Elemento O, Kharas MG, Jaffrey S, Scott D, Khelashvili G, Meyer-Hermann M, Victora G, Melnick A. BTG1 mutation yields supercompetitive B cells primed for malignant transformation. Science. 2023;379.
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Citing

If you use the information or data from this site, please cite

Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.

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