Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor

Noriko Wada, Yukinori Kurokawa, Tsuyoshi Takahashi, Takuya Hamakawa, Seiichi Hirota, Tetsuji Naka, Yasuhiro Miyazaki, Tomoki Makino, Makoto Yamasaki, Kiyokazu Nakajima, Shuji Takiguchi, Masaki Mori, Yuichiro Doki

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24 Citations (Scopus)

Abstract

Objective: Imatinib is a standard treatment for metastatic gastrointestinal stromal tumor (GIST). Imatinib resistance is mostly caused by secondary mutations in C-KIT. The antitumor effect of second-line agents is correlated with the type of secondary mutation: indeed, sunitinib is effective against tumors with C-KIT exon 13 or 14 mutations. We investigated whether secondary C-KIT mutations can be detected in circulating tumor DNA (ctDNA) from peripheral blood. Methods: This study included 4 patients who underwent resection of imatinib-resistant GIST. Tumor-specific mutations in each tumor were determined by Sanger sequencing. ctDNA was extracted from peripheral blood obtained before and after the treatment of imatinib-resistant lesions. Each of the secondary target mutations in ctDNA was investigated, using a next-generation sequencer. Results: Imatinib-resistant lesions had single-nucleotide substitutions in C-KIT exon 13 in 3 patients and exon 18 in 1 patient. Identical secondary C-KIT mutations could be detected in ctDNA with a mutant fraction range of 0.010-9.385%. One patient had growth of an imatinib-resistant tumor containing a C-KIT exon 13 mutation, and the fraction of ctDNA decreased after initiation of sunitinib. Conclusion: Detection of secondary C-KIT mutations in ctDNA could be useful for the selection of targeted agents and prediction of antitumor effects.

Original languageEnglish
Pages (from-to)112-117
Number of pages6
JournalOncology (Switzerland)
Volume90
Issue number2
DOIs
Publication statusPublished - Feb 1 2016
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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