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Promoter Methylation of the CADM1 and 4.1B Genes Occurs Independently of the EGFR or the KRAS2 Mutation in Non-Small Cell Lung Cancer

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DOI: 10.4236/jct.2015.63030    2,808 Downloads   3,279 Views  

ABSTRACT

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 4.1showed 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.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Kogai, H. , Kikuchi, S. , Obana, T. , Tsuboi, Y. , Maruyama, T. , Sakurai-Yageta, M. , Asamura, H. , Kanai, Y. and Murakami, Y. (2015) Promoter Methylation of the CADM1 and 4.1B Genes Occurs Independently of the EGFR or the KRAS2 Mutation in Non-Small Cell Lung Cancer. Journal of Cancer Therapy, 6, 273-285. doi: 10.4236/jct.2015.63030.

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