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

Research output: Contribution to journalArticle

17 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

Fingerprint

Gastrointestinal Stromal Tumors
Mutation
Neoplasms
Exons
DNA
Imatinib Mesylate
Antineoplastic Agents
Nucleotides

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor. / Wada, Noriko; Kurokawa, Yukinori; Takahashi, Tsuyoshi; Hamakawa, Takuya; Hirota, Seiichi; Naka, Tetsuji; Miyazaki, Yasuhiro; Makino, Tomoki; Yamasaki, Makoto; Nakajima, Kiyokazu; Takiguchi, Shuji; Mori, Masaki; Doki, Yuichiro.

In: Oncology (Switzerland), Vol. 90, No. 2, 01.02.2016, p. 112-117.

Research output: Contribution to journalArticle

Wada, N, Kurokawa, Y, Takahashi, T, Hamakawa, T, Hirota, S, Naka, T, Miyazaki, Y, Makino, T, Yamasaki, M, Nakajima, K, Takiguchi, S, Mori, M & Doki, Y 2016, 'Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor', Oncology (Switzerland), vol. 90, no. 2, pp. 112-117. https://doi.org/10.1159/000442948
Wada, Noriko ; Kurokawa, Yukinori ; Takahashi, Tsuyoshi ; Hamakawa, Takuya ; Hirota, Seiichi ; Naka, Tetsuji ; Miyazaki, Yasuhiro ; Makino, Tomoki ; Yamasaki, Makoto ; Nakajima, Kiyokazu ; Takiguchi, Shuji ; Mori, Masaki ; Doki, Yuichiro. / Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor. In: Oncology (Switzerland). 2016 ; Vol. 90, No. 2. pp. 112-117.
@article{4b671f09df684274a4534a6f4b6fa31f,
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. Conclusion: Detection of secondary C-KIT mutations in ctDNA could be useful for the selection of targeted agents and prediction of antitumor effects.",
author = "Noriko Wada and Yukinori Kurokawa and Tsuyoshi Takahashi and Takuya Hamakawa and Seiichi Hirota and Tetsuji Naka and Yasuhiro Miyazaki and Tomoki Makino and Makoto Yamasaki and Kiyokazu Nakajima and Shuji Takiguchi and Masaki Mori and Yuichiro Doki",
year = "2016",
month = "2",
day = "1",
doi = "10.1159/000442948",
language = "English",
volume = "90",
pages = "112--117",
journal = "Oncology",
issn = "0030-2414",
publisher = "S. Karger AG",
number = "2",

}

TY - JOUR

T1 - Detecting Secondary C-KIT Mutations in the Peripheral Blood of Patients with Imatinib-Resistant Gastrointestinal Stromal Tumor

AU - Wada, Noriko

AU - Kurokawa, Yukinori

AU - Takahashi, Tsuyoshi

AU - Hamakawa, Takuya

AU - Hirota, Seiichi

AU - Naka, Tetsuji

AU - Miyazaki, Yasuhiro

AU - Makino, Tomoki

AU - Yamasaki, Makoto

AU - Nakajima, Kiyokazu

AU - Takiguchi, Shuji

AU - Mori, Masaki

AU - Doki, Yuichiro

PY - 2016/2/1

Y1 - 2016/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84955615188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955615188&partnerID=8YFLogxK

U2 - 10.1159/000442948

DO - 10.1159/000442948

M3 - Article

C2 - 26779618

AN - SCOPUS:84955615188

VL - 90

SP - 112

EP - 117

JO - Oncology

JF - Oncology

SN - 0030-2414

IS - 2

ER -