Secondary mutations in C-KIT in GIST occuring after therapy with imatinib

Konference: 2013 The 9th Symposium & Workshop on Molecular Pathology and Histo(cyto)chemistry

Kategorie: Gastrointestinální nádory

Téma: Invited guests

Číslo abstraktu: 16

Autoři: Mgr. Jitka Berkovcová, Ph.D.; Mgr. Hana Jiřikovská; MUDr. Eva Krejčí; MUDr. Ilona Kocáková, Ph.D.; MUDr. Lukáš Sirotek; RNDr. Eva Macháčková, Ph.D.; MUDr. Pavel Fabián, Ph.D.

Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors. They are characterized by a strong tyrozinkinase receptor C-kit expression (CD 117), which is the most important immunohistochemical marker. Along with its high expression activating mutations in C-KIT gene are detected. Approximately 5-10% of GIST do not express C-kit, they display more frequently mutations in PDG FR a gene, which also encodes the C-kit related tyrosine kinase receptor type III . To determine the mutation status of C-KIT and PDG FR a genes we have introduced a direct sequencing method of the most frequently mutated exons. Treatment of GIST is based on primary resection. For the treatment of inoperable or metastatic disease there are two biological agents: imatinib (Glivec) and sunitinib (Sutent) in the Czech Republic. Imatinib is indicated in patients with C-kit positive GIST. Sunitinib is used in patients in whom treatment with imatinib has failed due to resistance or intolerance. We report a case report of a patient with histologically confirmed GIST with a high risk for aggressive behavior, C-kit positive. The patient was after total exision. The metastases in the liver were observed. Then she was deployed targeted biological therapy (Glivec 400 mg / day). After a month of therapy was reported a partial regression of disease, which further progressed to induce stabilization of residual liver metastases. After a four year period of stable dinase, a new tumor in a stomach wall was detected by CT scans. A surgical revision was indicated, leading to a resection of two tumors in a stomach wall and a near adipose tissue. The first one was evaluated as GIST with a high risk of aggressive behavior by a pathologist. The second one affecting the adipose tissue was characterised by hypocellularity with weak C-kit positivity. Molecular examination of both samples showed the presence of a large deletion mutation in exon 11 of the C-KIT gene (p.Trp557_Gln575del19), the same mutation was subsequently found from the initial biopsy of liver metastases obtained before the deployment of targeted therapy. Furthermore, in the new GIST focus a secondary point mutation in exon 17 of the C-KIT gene (p.Cys809Gly) was detected, which was not found in the original liver biopsy. In our presentation we want to demonstrate the importance of multidisciplinary collaboration with the oncologist, surgeon and molecular biologist, pathologist in the diagnosis and especially individual approach to patients.

Datum přednesení příspěvku: 26. 4. 2013