Promoter Methylation of the <i>CADM</i>1 and 4.1<i>B</i>Genes Occurs Independently of the <i>EGFR</i>or the <i>KRAS</i>2 Mutation in Non-Small Cell Lung Cancer

• 作者: Hiroyuki Kogai Hisao Asamura Mika Sakurai-Yageta Shinji Kikuchi Takashi Obana Tomoko Maruyama Yae Kanai Yoshinori Murakami Yumi Tsuboi
• 来源期刊: 癌症治疗(英文)
• 学科: 医学
• 关键词: Non-Small Cell Lung Cancer EGFR MUTATION KRAS MUTATION CADM1 METHYLATION 4.1B METHYLATION
• 年，卷（期）: azzlyw_2015,（3）
• 页码范围: 273-285
• 页数: 13页
• 分类号: R73

摘要

Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent approach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI varies in individual cases even among tumors carrying the same?EGFR?mutation, suggesting the involvement of modifying factors. To characterize possible modifiers, we examined mutation state of the?EGFR?and the?KRAS?genes in Japanese NSCLC and compared them with the methylation state of lung tumor suppressors, the?CADM1 and?4.1B,?whose products have potentials to modify the functions of EGFR or KRAS. Materials and methods: A total of 103 Japanese NSCLC and 11 NSCLC cell lines were examined. Genomic DNA of exons 18–21 of the?EGFR?and exons 1 and 2 of the?KRAS?were amplified by polymerase chain reaction (PCR), followed by single-strand conformation polymorphism analysis and direct sequencing. Methylation status of gene promoters in NSCLC cells were examined by methylation-specific PCR. Results: Mutations of the?EGFR?and?KRAS?were detected mutually exclusively in 27 and 11 out of 103 NSCLC cases, respectively.?EGFR?mutations were observed exclusively in adenocarcinoma (27 of 69, 41%) and preferentially in tumors from female and non-smokers (p < 0.00001). Eight (30%) and 12 (44%) of 27 tumors carrying mutated?EGFR?and 4 (36%) and 8 (73%) of 11 tumors carrying mutated?KRAS?showed methylation of the?CADM1 and 4.1B, respectively.?EGFR-mutated tumors with methylation of either?CADM1 or 4.1B?showed more malignant features than those with unmethylated?CADM1 and 4.1B?(p < 0.05). Conclusion: Methylation state of the?CADM1 and?4.1B?are independent of the mutation status of the?EGFR?or?KRAS?but play roles in the malignant progression of NSCLC. Integration of epigenetic information would be useful for identifying possible modifiers to predict the response or recurrence of lung adenocarcinoma to the EGFR-TKI therapy.