title: Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor.
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.
  
  
  CONCLUSIONS
  Detection of secondary C-KIT mutations in ctDNA could be useful for the selection of targeted agents and prediction of antitumor effects.
authors.affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Wada
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Kurokawa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Hamakawa
authors.forename: Seiichi
authors.initials: S
authors.lastname: Hirota
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Naka
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Tomoki
authors.initials: T
authors.lastname: Makino
authors.forename: Makoto
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Nakajima
authors.forename: Shuji
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Masaki
authors.initials: M
authors.lastname: Mori
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Doki
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis* / Q000097:blood; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000097:blood / Q000188:drug therapy / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit