Table of Contents
One study reported BTK mutations in approximately 7% of FL and 11% of transformed FL cases.1 Another showed these mutations were more common, and typically co-occur in tumours with BCL2 translocations. Despite the known role of certain BTK mutations in acquired resistance to BTK inhibitors, these mutations were found in BTK inhibitor-naïve patients.2 These mutations often occur in treatment-naive patients and lead to inactivation of the BTK protein through destabilization or by altering key residues involved in enzymatic activity.1 The mutation pattern in DLBCL and FL implies the preferential accumulation of inactivating mutations3,4. No notable hot spots have been described in this gene in the context of the cancers listed below.

Experimental Evidence

Driver mutations affecting this gene in FL/DLBCL have been experimentally demonstrated to cause a reduction or loss of function (LOF).3

Clinical Relevance

The BTK inhibitor Imbruvica (Ibrutinib) had prior FDA approval for use in MCL and MZL which has since been withdrawn because primary outcomes from the confirmatory Phase 3 studies studies were considered insufficient to support conversion to full approval. There are some data suggesting a subset of DLBCL patients (with certain genetic features) may benefit from the combination of Ibrutinib with R-CHOP5. There is no known relevance between BTK mutations and the activity of BTK inhibitors.

Relevance tier by entity

Entity Tier Description
DLBCL 1 High-confidence DLBCL gene
FL 1 High-confidence FL gene

Mutation incidence in large patient cohorts (GAMBL reanalysis)

DLBCL

Entity Collection N mutated Incidence 95% CI
DLBCL GAMBL without Reddy 1,089 43 0.0395 [0.0279,0.0511]
DLBCL GAMBL with Reddy 2,088 74 0.0354 [0.0275,0.0434]
DLBCL BC 231 13 0.0563 [0.0266,0.086]
DLBCL Dana-Farber 303 9 0.0297 [0.0106,0.0488]
DLBCL NCI 470 16 0.0340 [0.0176,0.0504]
DLBCL Reddy 999 31 0.0310 [0.0203,0.0418]
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 66 0.0555 [0.0425,0.0685]
FL BC 379 24 0.0633 [0.0388,0.0878]
FL Kalmbach 164 8 0.0488 [0.0158,0.0817]
FL Crouch 547 27 0.0494 [0.0312,0.0675]
FL FL_ICGC 99 7 0.0707 [0.0202,0.1212]

Mutation pattern and selective pressure estimates

Entity Missense dN/dS Nonsense dN/dS Q value
BL 0.8909 7.5037 1
FL 8.8305 32.9665 0
DLBCL 14.1622 19.5227 0

Visualizations

Protein

View coding variants in ProteinPaint hg19 or hg38

Genome

View all variants in GenomePaint hg19 or hg38

Expression

History

%%{init: { 'logLevel': 'debug', 'theme': 'dark' } }%% timeline title Publication timing 2017-01-26 : Krysiak : FL 2017-05-01 : Albuquerque : DLBCL 2017-10-10 : Reddy : DLBCL

References

1.
Krysiak K, Gomez F, White BS, Matlock M, Miller CA, Trani L, Fronick CC, Fulton RS, Kreisel F, Cashen AF, Carson KR, Berrien-Elliott MM, Bartlett NL, Griffith M, Griffith OL, Fehniger TA. Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma. Blood. 2017 Jan 26;129(4):473–483. PMCID: PMC5270390
2.
Albuquerque MA, Grande BM, Ritch EJ, Pararajalingam P, Jessa S, Krzywinski M, Grewal JK, Shah SP, Boutros PC, Morin RD. Enhancing knowledge discovery from cancer genomics data with Galaxy. Gigascience. 2017 May 1;6(5):1–13. PMCID: PMC5437943
3.
Hu N, Wang F, Sun T, Xu Z, Zhang J, Bernard D, Xu S, Wang S, Kaminski M, Devata S, Phillips T, Malek SN. Follicular Lymphoma-associated BTK Mutations are Inactivating Resulting in Augmented AKT Activation. Clin Cancer Res. 2021 Apr 15;27(8):2301–2313. PMCID: PMC8046715
4.
Schejbel L, Breinholt MF, Gang AO, Nielsen TH, Pedersen LM, Høgdall E, Nørgaard P. Inactivating BTK mutations in large B-cell lymphoma in a real-world cohort: Strong correlation with BCL2 translocation. EJHaem. 2022 Aug;3(3):936–939. PMCID: PMC9421985
5.
Wilson WH, Wright GW, Huang DW, Hodkinson B, Balasubramanian S, Fan Y, Vermeulen J, Shreeve M, Staudt LM. Effect of ibrutinib with R-CHOP chemotherapy in genetic subtypes of DLBCL. Cancer Cell. 2021 Dec 13;39(12):1643–1653.e3. PMCID: PMC8722194
6.
Reddy A, Zhang J, Davis NS, Moffitt AB, Love CL, Waldrop A, Leppa S, Pasanen A, Meriranta L, Karjalainen-Lindsberg ML, Nørgaard P, Pedersen M, Gang AO, Høgdall E, Heavican TB, Lone W, Iqbal J, Qin Q, Li G, Kim SY, Healy J, Richards KL, Fedoriw Y, Bernal-Mizrachi L, Koff JL, Staton AD, Flowers CR, Paltiel O, Goldschmidt N, Calaminici M, Clear A, Gribben J, Nguyen E, Czader MB, Ondrejka SL, Collie A, Hsi ED, Tse E, Au-Yeung RKH, Kwong YL, Srivastava G, Choi WWL, Evens AM, Pilichowska M, Sengar M, Reddy N, Li S, Chadburn A, Gordon LI, Jaffe ES, Levy S, Rempel R, Tzeng T, Happ LE, Dave T, Rajagopalan D, Datta J, Dunson DB, Dave SS. Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma. Cell. 2017 Oct;171(2):481–494.e15. PMCID: PMC5659841

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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