TITLE:
Promoter Methylation of the CADM1 and 4.1B Genes Occurs Independently of the EGFR or the KRAS2 Mutation in Non-Small Cell Lung Cancer
AUTHORS:
Hiroyuki Kogai, Shinji Kikuchi, Takashi Obana, Yumi Tsuboi, Tomoko Maruyama, Mika Sakurai-Yageta, Hisao Asamura, Yae Kanai, Yoshinori Murakami
KEYWORDS:
Non-Small Cell Lung Cancer, EGFR Mutation, KRAS Mutation, CADM1 Methylation, 4.1B Methylation
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.3,
March
17,
2015
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 sameEGFRmutation, suggesting the
involvement of modifying factors. To characterize possible modifiers, we
examined mutation state of theEGFRand theKRASgenes
in Japanese NSCLC and compared them with the methylation state of lung tumor
suppressors, theCADM1 and4.1B,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 theEGFRand exons 1 and 2 of
theKRASwere 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 theEGFRandKRASwere
detected mutually exclusively in 27 and 11 out of 103 NSCLC cases,
respectively.EGFRmutations were observed exclusively in
adenocarcinoma (27 of 69, 41%) and preferentially in tumors from female and
non-smokers (p EGFRand 4 (36%) and 8 (73%) of 11 tumors carrying
mutatedKRASshowed methylation of theCADM1 and
4.1B, respectively.EGFR-mutated tumors with methylation of
eitherCADM1 or 4.1Bshowed more malignant features
than those with unmethylatedCADM1 and 4.1B(p CADM1 and4.1Bare
independent of the mutation status of theEGFRorKRASbut
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.