CpG Island Methylator Phenotype Involving Tumor Suppressor Genes Located On Chromosome 3p In Non-Small Cell Lung Cancer

Objective: We addressed the question of whether CpG island methylator phenotype (CIMP) status could correlate with non-small cell lung cancer (NSCLC) and be a good biomarker for early detection and evaluating prognosis of NSCLC. Methylation profiles for eight tumor suppressor genes (TSGs) harbored in chromosome 3p were detected in 60 NSCLC tissues, 60 paired normal tissues and 56 blood samples from NSCLC patients as well as 78 normal blood samples.Methods: Using methylation-specific PCR (MSP) method, we examined methylation profiles for eight TSGs harbored in chromosome 3p in 60 NSCLC tissues and 60 paired normal tissues and 56 NSCLC blood samples as well as 78 normal blood samples. CIMP positive is referred to having four or more than four synchronously methylated genes per sample.Results: 59 of 60 (98.3%) NSCLCs presented promoter methylation of at least one gene while only one malignant tumor showed no methylation of any of eight genes. The frequency of promoter methylation for eight genes explored ranged from 12% for hMLH1 to 67% for RASSF1A given that of VHL (none) was not considered in solid tissues. Interestingly, CIMP+ was found in 56.7% (34/60) of NSCLC and in 6.7% (4/60) of paired normal tissues, respectively. In the following methylation study on peripheral blood, CIMP+ was found in 37.5% (21/56) of blood samples from NSCLC patients and 6.4% (5/78) of normal blood samples, respectively (Given that VHL and hMLH1 showed no methylation of any sample, we didn't consider the contribution of the two gene to CIMP+); CIMP? was present in 43.3% (26/60) of NSCLC and 93.3% (56/60) of paired normal tissues, and 62.5% (35/56) of blood samples from NSCLC patients as well as 93.6% (73/78) normal blood samples, respectively. The data suggest that CIMP status was significantly associated with NSCLC and paired normal tissues (P<0.001), the blood samples from NSCLC patients and normal blood samples (P<0.001). In addition, there appeared to be a significant association between CIMP status and survival prognosis of NSCLC (P=0.0166), CIMP status of peripheral blood leucocyte DNA could an increased risk factor in NSCLC (OR 8.76 [95% CI 2.85-31.68], P<0.001).Conclusion: To our knowledge, for the first time, the present study sheds light on the presence of chromosome 3p-specific CIMP, which might play an important role in tumorigenesis of NSCLC. Importanly, this study suggests that leucocyte DNA hypermetylation of TSGs, including hOGG1 and RASSF1A, could provide useful biomarkers of susceptibility to NSCLC. Further reseach is warranted to confirm these findings.