Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790: Implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer

Akiko Fujii, Taishi Harada, Eiji Iwama, keiichi ota, Kazuto Furuyama, Kayo Ijichi, Tatsuro Okamoto, Isamu Okamoto, Koichi Takayama, Yoichi Nakanishi

研究成果: ジャーナルへの寄稿記事

9 引用 (Scopus)

抄録

Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8%. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment.

元の言語英語
ページ(範囲)271-278
ページ数8
ジャーナルCancer Genetics
208
発行部数5
DOI
出版物ステータス出版済み - 5 1 2015

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5-Methylcytosine
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Codon
Mutation
Cytosine
DNA Methylation
Protein-Tyrosine Kinases
Cell Line
Deamination
Inborn Genetic Diseases
Methylation
Exons
Neoplasms
Lymph Nodes
DNA

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

これを引用

Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790 : Implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. / Fujii, Akiko; Harada, Taishi; Iwama, Eiji; ota, keiichi; Furuyama, Kazuto; Ijichi, Kayo; Okamoto, Tatsuro; Okamoto, Isamu; Takayama, Koichi; Nakanishi, Yoichi.

:: Cancer Genetics, 巻 208, 番号 5, 01.05.2015, p. 271-278.

研究成果: ジャーナルへの寄稿記事

Fujii, Akiko ; Harada, Taishi ; Iwama, Eiji ; ota, keiichi ; Furuyama, Kazuto ; Ijichi, Kayo ; Okamoto, Tatsuro ; Okamoto, Isamu ; Takayama, Koichi ; Nakanishi, Yoichi. / Hypermethylation of the CpG dinucleotide in epidermal growth factor receptor codon 790 : Implications for a mutational hotspot leading to the T790M mutation in non-small-cell lung cancer. :: Cancer Genetics. 2015 ; 巻 208, 番号 5. pp. 271-278.
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abstract = "Nearly one half of all cases of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for non-small-cell lung cancer (NSCLC) are due to the T790M mutation in EGFR exon 20. The T790M mutation is a C→T transition mutation at a CpG dinucleotide. DNA methylation of cytosine (5-methylcytosine (5-mC)) in CpG dinucleotides is a common DNA modification; CpG dinucleotides are considered to be mutational hotspots that cause genetic diseases and cancers through spontaneous deamination of 5-mC, resulting in C→T transition mutations. This study aimed to examine the methylation level of cytosine of EGFR codon 790 and investigate whether DNA methylation was involved in acquiring the T790M mutation. We examined 18 NSCLC tumor tissues, 7 normal lymph node tissues, and 4 NSCLC cell lines (PC9, HCC827, 11-18, and A549). 5-mC was checked by bisulfite sequencing and quantified by pyrosequencing. We found that all tissue samples and cell lines had 5-mC in EGFR codon 790. The 5-mC range was 58.4-90.8{\%}. Our results imply that hypermethylation of the CpG dinucleotide in EGFR codon 790 leads to the C→T transition mutation, causing resistance to EGFR-TKI treatment.",
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