Abstract
Gene methylation has been frequently observed in lung cancer. However, the use of methylated genes in bronchial aspirates of patients with lung cancer remains to be evaluated. The purpose of this study was to analyze whether the detection of genes with aberrant promoter methylation can be useful noninvasive biomarkers in bronchial aspirates from lung cancer. We found that the methylation status of the cyclin-dependent kinase inhibitor 2A (P16), Ras association domain family 1 isoform (RASSF1A), adenomatous polyposis coli (APC) and short stature homeobox 2 (SHOX2) genes was significantly correlated with lung cancer in bronchial aspirates. The P16, RASSF1A and APC methylation had a bad diagnostic effect in bronchial aspirates of patients with lung cancer compared with non-tumor controls (P16: sensitivity = 0.26, specificity = 0.99, area under the curve (AUC) = 0.67; RASSF1A: sensitivity = 0.40, specificity = 0.99, AUC = 0.66; APC: sensitivity = 0.17, specificity = 0.98, AUC = 0.65). The pooled sensitivity, specificity, and AUC of the SHOX2 methylation were 0.75, 0.94, and 0.94, respectively. Moreover, when squamous cell carcinoma (SCC) was compared to adenocarcinoma (AC), the SHOX2 gene had a significantly higher methylation rate in SCC than in AC (P < 0.001). Methylated P16, RASSF1A, APC and retinoic acid receptor beta2 (RARβ2) genes had similar frequencies in these two histotypes (P > 0.1). Our findings suggest that methylated SHOX2 gene could be a specific and potential noninvasive biomarker using bronchial aspirates for lung cancer diagnosis, especially for SCC.
Highlights
Lung cancer is the most common human malignant tumor and causes the highest number of cancer-related deaths worldwide
We found that the methylation status of the cyclin-dependent kinase inhibitor 2A (P16), Ras association domain family 1 isoform (RASSF1A), adenomatous polyposis coli (APC) and short stature homeobox 2 (SHOX2) genes was significantly correlated with lung cancer in bronchial aspirates
The results from bronchial aspirates showed that a significant correlation was observed between the methylation of the P16 (OR = 8.15, 95% confidence interval (95% CI) = 3.18 - 20.87, P < 0.001), RASSF1A (OR = 32.60, 95% CI = 19.21 - 55.32, P < 0.001), APC (OR = 11.88, 95% CI = 4.75 - 29.72, P < 0.001) and SHOX2 (OR = 50.10, 95% CI = 30.30 - 82.84, P < 0.001) genes with lung cancer in more than four studies, including 840 lung cancer patients and 800 controls (Figure 2), 980 lung cancer patients and 733 controls (Figure 3), 360 patients with lung cancer and 273 controls (Figure 4), and 493 patients with lung cancer and 415 controls (Figure 4), respectively
Summary
Lung cancer is the most common human malignant tumor and causes the highest number of cancer-related deaths worldwide. Lung carcinoma encompasses non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The former accounts for approximately 85% of cases of lung cancer, mainly consisting of adenocarcinoma (AC) and squamous cell carcinoma (SCC) [2, 3]. Accumulating evidence has shown that DNA methylation, a major molecular mechanism of epigenetic changes, is correlated with human malignant tumors, including lung cancer [4,5,6,7]. Genes with aberrant DNA methylation can be noninvasive biomarkers for the detection and diagnosis of cancer [8,9,10]. Methylated genes were found in body fluid samples, such as plasma, urine, sera, and sputum, indicating that DNA methylation had the potential value as a biomarker in non-invasive cancer screening and diagnosis [11,12,13]
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