Promoter methylation of APC and RAR-β genes as prognostic markers in non-small cell lung cancer (NSCLC)
Introduction
Lung cancer is the leading cause of cancer-related deaths in the world. Lung cancer survival tends to be poorer in developing countries as a result of increasing use of tobacco product compared with developed countries (Jemal et al., 2011, Molina et al., 2008). Non-small cell lung cancer (NSCLC) comprises the majority (85–90%) of lung cancer (Zhang et al., 2011b). Despite advances in the detection and treatment of NSCLC, the overall 5-year survival rate remains under 15% (Kim et al., 2006). The poor outcome of NSCLC patients may be attributed partially to late diagnosis and tumor recurrence (Henschke et al., 2006). Thus, developing new markers for early diagnosis and prognostic prediction may help to improve survival rate and life quality of patients with NSCLC.
DNA methylation is an epigenetic modification causing the silence of target genes, and can be induced by environmental factors such as exposure to smoking (Salskov et al., 2011). The silencing of tumor suppressor genes by promoter methylation is a common mechanism in the genesis of human cancers (Cheishvili et al., 2014). As promising biomarkers for early detection of NSCLC, methylation of multiple genes has been studied, including CADM1, CDH1, CDH13, p16, GSTP1, MGMT, and RASSF1A (Zhang et al., 2011b, Ji et al., 2011, Anglim et al., 2008). Moreover, methylation of some tumor suppressor genes has also been studied for prognosis in different cancers. For example, Henrique et al. (2007) reported that high promoter methylation levels of Adenomatous polyposis coli (APC) gene predict poor prognosis in prostate cancer patients, and Chen and Chiu (2009) showed that methylation in the APC promoter may serve as a predictor for the prognosis of Taiwanese colorectal cancer patients. In patients with stage I NSCLC, Kim et al. (2006) suggested that cohypermethylation of p16 and FHIT genes may be a valuable biomarker for predicting the recurrence-associated prognosis of the disease. Saito et al. (2010) reported that LINE-1 hypomethylation was an independent marker of poor prognosis in stage IA NSCLC.
APC and retinoic acid receptor-beta (RAR-β) are two important tumor suppressor genes (Houle et al., 1993, Virmani and Gazdar, 2003). However, Khuri et al. (2000) demonstrated that strong expression of RAR-β correlated with worse outcome of early-stage NSCLC. In addition, Brabender et al. (2001) reported that high APC promoter methylation is associated with inferior survival whereas Safar et al. (2005) showed that patients whose tumors were hypermethylated at APC enjoyed substantially longer 1- and 2-year survival using recursive partitioning. Additional studies are needed to elucidate the prognostic values of the methylation status of these two genes. Here we examined the methylation status of APC and RAR-β promoters in tumor tissue and corresponding non-tumor lung tissue in a cohort of 41 Chinese patients with NSCLC, and analyzed whether the methylation of APC or RAR-β, combined with or without other clinicopathological variables, could be used to predict the clinical outcomes of patients with primary NSCLC after surgical resection.
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Patients
Clinicopathological characteristics of the participated patients are presented in Table 1. All tumors were completely resected (R0 category). Patients with histopathological stage IIIa tumors received postoperative chemotherapy. The median follow-up was 18 months (min. 0.2; max. 60 months) and no patient was lost to follow-up. Histologically normal lung tissue specimens obtained at surgery from 8 patients with no evidence of cancer were included as a control group. All patients provided written
DNA methylation profile of APC and RAR-β
We determined the methylation status of the promoters of two genes, APC and RAR-β, in tumor tissue and corresponding non-neoplastic lung tissue of 41 NSCLC patients, and in 8 non-tumor patients (Table 2). Based on the DNA methylation profile of APC and RAR-β, we found that while there was no obvious relationship between APC methylation and tumor tissue, there was a significant correlation between RAR-β methylation status and tumor tissue, with a P-value of 0.049. In addition, the methylation of
Discussion
In this study, we detected the methylation status of APC and RAR-β promoters in tumor tissue and corresponding non-tumor lung tissue in 41 Chinese primary NSCLC patients and 8 non-cancer patients using methylation specific PCR, and further analyzed the diagnosis and prognosis value of the promoter methylation of APC and RAR-β in NSCLC patients.
While there was no obvious relationship between APC methylation and tumor tissue, higher occurrence of RAR-β methylation in tumor tissue than in
Acknowledgment
This work was supported by a grant from the National Key Clinical Specialty Construction Program[2011]873.
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Contributed equally.