BTK

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 mutations^3,4. 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The BTK inhibitor Imbruvica (Ibrutinib) had prior FDA approval for use in MCL and MZL which has since been withdrawn because primary outcomes from the confirmatory Phase 3 studies studies were considered insufficient to support conversion to full approval.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.

Relevance tier by entity

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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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Expression

History

References