W515L

W515L is a missense mutation in the PDGFRA gene, resulting in the substitution of tryptophan with leucine at amino acid position 515. It is described in the context of somatic alterations found in certain cancers rather than as a common germline variant.

The mutation has been reported in tumor samples from glioblastoma and gastrointestinal stromal tumors (GIST), among possible others. W515L is considered a activating or gain-of-function change that can lead to constitutive PDGFRA tyrosine kinase signaling, promoting downstream pathways such as PI3K/AKT and MAPK that contribute to tumor cell proliferation and survival.

Clinical and research implications of W515L center on targeted therapy. Because PDGFRA is a druggable kinase, tumors harboring this mutation may show sensitivity to PDGFRA-directed tyrosine kinase inhibitors (TKIs) such as imatinib and sunitinib in some cases, though responses are highly context-dependent and mutation-specific. Some PDGFRA alterations are associated with intrinsic resistance to certain TKIs, so the therapeutic outcome for W515L can vary between patients and tumor types.

Detection of W515L is typically accomplished through tumor DNA sequencing using targeted next-generation sequencing panels or exome sequencing. It is important to distinguish somatic mutations from potential germline variants in clinical interpretation.

Overall, W515L is a rare PDGFRA mutation with potential implications for targeted therapy, but its prognostic significance and predictive value for TKI response require further study and may differ across tumor types.