PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations.

摘要: Activating mutations in the platelet-derived growth factor (PDGF) receptor alpha (PDGFRA) have been described patients with gastrointestinal stromal tumors or myeloid malignancies associated hypereosinophilia. These respond well to imatinib mesylate, raising question as whether a PDGF mutation other tumor types should receive tyrosine kinase inhibitor treatment. We characterized 10 novel somatic point PDGFRA that reported isolated cases of glioblastoma, melanoma, acute leukemia, peripheral nerve sheath and neuroendocrine carcinoma. The transmembrane domain V536E stimulated Ba/F3 cell signaling via ERK STAT5 absence ligand. This mutant, identified was strongly inhibited by imatinib. Modeling suggested modulates packing helices dimer. By contrast, two highly conserved residues affected traffic surface activity, thereby preventing response PDGF. had no significant impact on activity. functional analysis matched predictions SIFT PolyPhen for only five these algorithms do not discriminate gain from loss function. Finally, an E996K variant melanoma line expressed cells. Altogether, several newly activate may therefore represent passenger mutations. Our results also underline importance characterizing alterations cancer patients.