C-Kit and PDGFRA

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Somatic KIT (C-Kit) and PDGFRA Genotyping

C-Kit Gene (exons 8, 9, 11, 13, 17 and 18) and PDGFRa (exons 12 and 18) Mutation Analysis

The KIT gene encodes the human homolog of the proto-oncogene c-kit, and the PDGFRA gene encodes a cell surface tyrosine kinase receptor for members of the platelet-derived growth factor family. Roughly 75%-85% of gastrointestinal stromal tumors (GIST) have activating mutations in c-kit, and an estimated 5%-7% have activating mutations in the PDGFRA gene¹. Tumors with mutations in exon 9 of the c-kit gene are associated with significantly shorter progression-free survival and overall survival compared to tumors with mutations in exon 11². However, it was found that tumors expressing an exon 9 mutation in c-kit had improved progression-free survival when given a high dose regimen of imatinib, compared to those with an exon 9 mutation who received regular dosing². Mutations in exon 12 and 18 of the PDGFRA gene have also been associated with responsiveness to imatinib. Specifically, two missense changes, D842V and D846V, in the PDGFRA gene are associated with resistance to imatinib¹, and the D561V mutation and deletions in exon 18 of the PDGFRA gene are associated to imatinib sensitivity¹.

Melanomas have also been noted to have activating mutations in the c-kit gene. About 15% of acral and 20% of mucosal melanomas have a c-kit alteration. Case reports have documented dramatic responses to imatinib in melanoma patients with c-kit mutations^3,4,5. Recently, an update on a multi-institutional phase II clinical trial of imatinib in melanoma patients at the International Melanoma Congress reported that none of the 10 wild-type c-kit cases had a clinical response, while five of the 10 patients with a c-kit mutation demonstrated a partial response to therapy⁶.