Abstract
Lung cancer remains the leading cause of cancer deaths worldwide. Although low-dose spiral computed tomography (LDCT) screening is used for the detection of lung cancer in a high-risk population, false-positive results of LDCT remain a clinical problem. Here, we developed a blood test of a novel panel of three established lung cancer methylation biomarkers for lung cancer detection. Short stature homeobox 2 gene (SHOX2), ras association domain family 1A gene (RASSF1A), and prostaglandin E receptor 4 gene (PTGER4) methylation was analyzed in a training cohort of 351 individuals (197 controls, 154 cases) and validated from an independent cohort of 149 subjects (89 controls, 60 cases). The novel panel biomarkers distinguished between malignant and benign lung disease at high sensitivity and specificity: 87.0% sensitivity [95% CI 80.2–91.5%], 98.0% specificity [95% CI 94.9–99.4%]. Sensitivity in adenocarcinoma, squamous cell carcinoma, small cell lung cancer, and other lung cancer was 89.0%, 87.5%, 85.7%, and 77.8%, respectively. Notably, cancer patients in stage I and II showed high diagnostic sensitivity at 82.5% and 90.5%, respectively. Moreover, the diagnostic efficiency did not show bias toward age, gender, smoking, and the presence of other (nonlung) cancers. The performance of the panel in the validation cohort confirmed the diagnostic value. These findings clearly showed that this panel of DNA methylation biomarkers was effective in detecting lung cancer noninvasively and may provide clinical utility in stand-alone or in combination with current imaging techniques to improve the diagnosis of lung cancer.
Highlights
Materials and methodsThe clinical study was designed and implemented in Henan Cancer Hospital using the Diagnostic Kit for Lung Cancer Genes Methylation (Excellen Medical Technology Co., Ltd.)
Lung cancer remains the leading cause of cancer deaths worldwide
We performed receiver operating characteristic (ROC) curve analysis to analyze the diagnostic efficacy of the stature homeobox 2 gene (SHOX2), ras association domain family 1A gene (RASSF1A) and, prostaglandin E receptor 4 gene (PTGER4) methylation in blood plasma
Summary
The clinical study was designed and implemented in Henan Cancer Hospital using the Diagnostic Kit for Lung Cancer Genes Methylation (Excellen Medical Technology Co., Ltd.). DNA isolation from plasma and bisulfite conversion using the Nucleic Acid Extraction Reagent (Excellen Medical Technology Co., Ltd.) according to the respective instructions for use. Bisulfite-modified DNA was used as a template for fluorescence-based RealTime PCR according to the instructions of the Diagnostic Kit for Lung Cancer Genes Methylation (Excellen Medical Technology Co., Ltd.)[26]. The PCR assay detected methylated SHOX2, RASSF1A, and PTGER4 DNA as targets and ACTB DNA as internal control, to assess the adequacy of input DNA This co-amplified internal control monitored the sample quality, preparation, and adequate DNA concentration of the sample. Real-time PCR data were analyzed using the Lung Cancer Analysis software v2.2 (Excellen Medical Technology Co., Ltd.)[26].
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