Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer

Abstract

Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARβ and p16 INK4A) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues ( P ⩽ 0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14 ARF, MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequent in cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues ( P < 0.001), and CIMP+ was associated with advanced stage ( P = 0.017), lymphatic metastasis ( P = 0.001) and adverse 2-year progression-free survival ( P = 0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified.