Journal of Cancer Therapy, 2015, 6, 273-285 Published Online March 2015 in SciRes. http://www.scirp.org/journal/jct http://dx.doi.org/10.4236/jct.2015.63030 How to cite this paper: Kogai, H., et al. (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. http://dx.doi.org/10.4236/jct.2015.63030 Promoter Methylation of the CADM1 and 4.1B Genes Occurs Independently of the EGFR or the KRAS2 Mutation in Non-Small Cell Lung Cancer Hiroyuki Kogai 1 , Shinji Kikuchi 1 , Takashi Obana 1 , Yumi Tsuboi 1 , Tomoko Maruyama 1 , Mika Sakurai-Yageta 1 , Hisao Asamura 2 , Yae Kanai 3 , Yoshinori Murakami 1* 1 Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan 2 Division of Thoracic Surgery, National Cancer Research Center Hospital, Tokyo, Japan 3 Division of Pathology, National Cancer Research Center Research Institute, Tokyo, Japan Email: * ymurakam@ims.u-tokyo.ac.jp Received 27 January 2015; accepted 13 March 2015; published 17 March 2015 Copyright © 2015 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ Abstract Objective: Targeting mutated EGFR by EGFR-tyrosine kinase inhibitors (EGFR-TKI) is a potent ap- proach to a subset of non-small cell lung cancer (NSCLC). However, the response to EGFR-TKI va- ries in individual cases even among tumors carrying the same EGFR mutation, suggesting the in- volvement 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 po- lymorphism 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 de- tected 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). Con- * Corresponding author.