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: Contribution to journalArticle査読

11 被引用数 (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.

本文言語英語
ページ(範囲)271-278
ページ数8
ジャーナルCancer Genetics
208
5
DOI
出版ステータス出版済み - 5 1 2015

All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 遺伝学
  • 癌研究

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