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Background: Both genetic and epigenetic changes in non-small cell lung cancer (NSCLC) are known to be a common event. Methods: Mutations in the epidermal growth factor receptor gene (EGFR), HER2, and KRAS, and the methylation profile of nine genes for NSCLC were analyzed and correlated with clinical and histologic data. Results: Thirty-nine EGFR, 4 HER2, and 6 KRAS mutations were found in 150 NSCLCs, with the methylation percentages of the genes ranging from 13% to 54%. Most mutations were present in adenocarcinomas, but mutations of the three genes were never present in individual tumors. The frequency of methylation for all the genes was correlated with the Methylation Index, a reflection of the overall methylation pattern (all genes, P< .01), supporting the presence of the CpG island methylator phenotype (CIMP) in NSCLC. On the basis of the methylation profile, CRBP1 and CDH13 methylation were good indicators of CIMP in NSCLC, and correlated with a poorer prognosis in adenocarcinomas. Mutations in EGFR, HER2, and KRAS were present exclusively, while methylation tended to be present synchronously. A comparison of mutation and methylation showed the EGFR mutation to have an inverse relationship with methylation of SPARC (secreted protein acidic and rich in cysteine) an extracellular Ca2+-binding matricellular glycoprotein associated with the regulation of cell adhesion and growth, and the p16INK4A gene. Conclusion: Our findings suggest that adenocarcinoma with CIMP have a poorer prognosis than adenocarcinoma without CIMP, and the EGFR mutation was shown to have an inverse relationship with methylation of SPARC and the p16INK4A gene in NSCLC.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]