In the present study, we found that promoter methylation of CALCA, EVX2, and PAX6 was significantly associated with PIK3CA amplification in NSCLC, however, such association was not seen with other gene methylation, suggesting that epigenetic alterations of these three genes may specifically occur as a consequence of overactivation of PI3K/Akt pathway in NSCLC. This evidence concerns the gene AKT1 and non-small cell lung carcinoma.