Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer

Noriko Hidaka, Eiji Iwama, Naoki Kubo, Taishi Harada, Kohta Miyawaki, Kentaro Tanaka, Isamu Okamoto, Eishi Baba, Koichi Akashi, Hiroyuki Sasaki, Yoichi Nakanishi

研究成果: ジャーナルへの寄稿記事

12 引用 (Scopus)

抄録

Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.

元の言語英語
ページ(範囲)75-82
ページ数8
ジャーナルLung Cancer
108
DOI
出版物ステータス出版済み - 6 1 2017

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erbB-1 Genes
Non-Small Cell Lung Carcinoma
Alleles
Mutation
Protein-Tyrosine Kinases
Polymerase Chain Reaction
Treatment Failure
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

これを引用

Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer. / Hidaka, Noriko; Iwama, Eiji; Kubo, Naoki; Harada, Taishi; Miyawaki, Kohta; Tanaka, Kentaro; Okamoto, Isamu; Baba, Eishi; Akashi, Koichi; Sasaki, Hiroyuki; Nakanishi, Yoichi.

:: Lung Cancer, 巻 108, 01.06.2017, p. 75-82.

研究成果: ジャーナルへの寄稿記事

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title = "Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer",
abstract = "Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1{\%} (range, 90.0–100{\%}). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7{\%} (range, 89.1–99.5{\%}). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.",
author = "Noriko Hidaka and Eiji Iwama and Naoki Kubo and Taishi Harada and Kohta Miyawaki and Kentaro Tanaka and Isamu Okamoto and Eishi Baba and Koichi Akashi and Hiroyuki Sasaki and Yoichi Nakanishi",
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T1 - Most T790M mutations are present on the same EGFR allele as activating mutations in patients with non–small cell lung cancer

AU - Hidaka, Noriko

AU - Iwama, Eiji

AU - Kubo, Naoki

AU - Harada, Taishi

AU - Miyawaki, Kohta

AU - Tanaka, Kentaro

AU - Okamoto, Isamu

AU - Baba, Eishi

AU - Akashi, Koichi

AU - Sasaki, Hiroyuki

AU - Nakanishi, Yoichi

PY - 2017/6/1

Y1 - 2017/6/1

N2 - Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.

AB - Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene (EGFR) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR. C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment.

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U2 - 10.1016/j.lungcan.2017.02.019

DO - 10.1016/j.lungcan.2017.02.019

M3 - Article

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SP - 75

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JO - Lung Cancer

JF - Lung Cancer

SN - 0169-5002

ER -