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PI3KD

From www.haematologyetc.co.uk



Gene affected:
PIK3C 𝛿 – phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic subunit Delta


Clinical significance
These proteins for part of the B-cell receptor signalling complex, and inhibition of the normal (unmutated) form has a therapeutic role in CLL and FCL.
However, mutations involving gain of function (type 1) or loss of regulation (type 2) are seen in an inherited immunodeficiency state, and the Type 1 mutations also underlie a range of acquired B cell and T cell disorders.
When associated with inherited immune deficiency these mutations have significant adverse outcome, but at present there is no clear prognostic evidence for somatic mutations.




Function of gene

These lipid kinases (phosphoinositide 3-kinases (PI3Ks)) form part of pathways responsible for a diverse range of cell functions including proliferation and survival. The protein encoded by this is found primarily in leukocytes. PIK3C 𝛿 binds p85 adapter proteins and GTP-bound RAS to initiate intracellular signalling. Inhibitors of PIK3C 𝛿 have been used in the treatment of CLL/SLL and follicular lymphoma. Inhibition by Idelalisib induces apoptosis and prevents proliferation in B cells by inhibiting several signalling pathways including BCR signalling, and CXCR4 and CXCR5 signalling which are involved in trafficking and homing of B –cells to the nodes and bone marrow.


NGS panel gene coverage

The panel covers the full coding sequence: Chr 18q12.3



Occurrence and significance


PIK3CD gain-of-function disorder
A rare genetic disorder starting in childhood with increased incidence of bacterial infection affecting the respiratory system or chronic viral infections (particularly EBV and CMV) and an increased risk of B-cell lymphomas. Lymphomas are mainly classical Hodgkin lymphoma or diffuse large B-cell lymphoma [DLBCL] although others are reported EBV-induced polymorphic lymphoproliferative disorders.
Somatic mutations in lymphoma
The same gain of function mutation may be associated with lymphoid malignancies, at this time information on expected frequency or prognosis is not available
B-cell lymphomas
DLBCL, mantle cell lymphoma, and rarely Burkitt lymphoma
T cell lymphomas
including acute lymphoblastic T-cell leukemia and hepatosplenic T-cell lymphoma



Links

GeneWiki link:
Gene Wiki entry for PIK3D
References
1. General reference