CpG island methylator phenotype involving chromosome 3p confers an increased risk of non-small cell lung cancer

Abstract

Purpose: This study aims to explore the association of CpG island methylator phenotype (CIMP) involving tumor suppressor genes on short arm of chromosome 3 (3p) with increased risk of non-small cell lung cancer (NSCLC).

Methods and materials: In this study, four NSCLC cell lines were cultured, and peripheral blood mononuclear cell (PBMC) specimens from 80 patients with NSCLC and 80 matched controls were collected for 3p-involved CIMP (3pCIMP) analysis. 3pCIMP was referred to as having at least three synchronously methylated genes of 3p per sample. Methylation-specific polymerase chain reaction was performed to examine the methylation status of each gene. DNA demethylation of NSCLC cell lines was achieved through the treatment with 5-aza-deoxycytidine. Logistic regression was used to assess odds ratios and 95% confidence intervals, which were adjusted for gender, age, and smoking status.

Results: Demethylation experiment showed that 3pCIMP status could play an important role in NSCLC cell proliferation. A total of 97.5% of PBMC specimens from NSCLC patients presented promoter methylation of any one of six genes (hOGG1, RAR-B, SEMA3B, RASSF1A, BLU, or FHIT) on 3p. Interestingly, 3pCIMP+ was found in 43.8% of NSCLC PBMC specimens and only in 6.3% of normal PBMC samples. The data suggest that 3pCIMP status is significantly associated with NSCLC and normal PBMC samples (p 0.001). More importantly, the results show that 3pCIMP positive carriers have a 12.8-fold increased risk of NSCLC (adjusted odds ratio, 12.8; 95% confidence interval, 4.38 -37.4, p 0.001) in Chinese population.

Conclusions: This is the first evidence of an association between PBMC 3pCIMP and risk for NSCLC.