Abstract
BackgroundLung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge. Furthermore, testing a single biomarker for the diagnosis of lung cancers is of relatively low effectiveness. Thus, a stronger diagnostic combination of blood biomarkers is needed to improve the diagnosis of non-small cell lung cancer (NSCLC).MethodsThe blood levels of individual biomarkers [IDH1, DNA methylation of short stature homeobox 2 gene (SHOX2), and prostaglandin E receptor 4 gene (PTGER4)] were measured and statistically analyzed in samples from healthy controls and patients with lung cancer. In total, 221 candidates were enrolled and randomly assigned into two groups for the training and validation of a diagnostic panel. Additionally, a subgroup analysis was performed in the whole cohort.ResultsA newly combined 3-marker diagnostic model for lung cancers was established and validated with area under the receiver operating characteristic (ROC) curve (AUC) values ranging from 0.835 to 0.905 in independent groups showing significantly stronger diagnostic value compared with a single tested biomarker. The sensitivity of the diagnostic model was as high as 86.1% and 80.0% in the training and validation sets, respectively. Although no apparent differences were found between the 3-marker and 2-marker models, the high clinical T-stage and histological type specificity of IDH1 and two other methylated DNA biomarkers were demonstrated in the subgroup analysis.ConclusionsThe combination of single biomarkers with high stage-specificity and histological type specificity (SHOX2 and PTGER4 DNA methylation and IDH1) showed better diagnostic performance in the detection of lung cancers compared with single marker assessment. A greater clinical utility of the panel may be developed by adding demographic/epidemiologic characteristics.
Highlights
Lung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge
The randomized National Lung Screening Trial has demonstrated the advantage of low-dose computed tomography (LDCT) compared to chest X-rays for screening lung cancers [2], annual screening was performed on only 4% of patients in high-risk populations [3]; its relatively lower specificity for indeterminate lung nodules, poor repeatability and related economic burden on the public health system increased the diagnostic cost for lung cancers
The prostaglandin E2 receptor 4 gene (PTGER4) product, EP4, is important in tumor progression mediated by prostaglandin E2 [19,20,21], which has been confirmed to have an upregulated expression in cancer tissues compared with that in normal tissues [20, 22]
Summary
Lung cancer is the leading cause of cancer-related death worldwide, and the timely and serial assessment of low-dose computed tomography (LDCT) in high-risk populations remains a challenge. Short stature homeobox 2 (SHOX2) gene DNA was confirmed to have higher methylation levels in patients with small cell lung cancer (SCLC) and squamous cell carcinoma (SCC) than in patients with adenocarcinoma (Ade) and in healthy controls [14,15,16], indicating its potential as a diagnostic biomarker for specific types of lung cancers. The discriminative ability in detection of lung cancers of the SHOX2/PTGER4 DNA methylation marker panel has been confirmed. It was concluded in a population containing relative higher percentage of nonAde lung cancers (Ade: non-Ade, 46:71) [23]. Isocitrate dehydrogenase 1 (IDH1) has been proven to have an important role in promoting tumor growth in NSCLC [24] and could be used as a blood biomarker for the detection of NSCLC, lung Ade [25]
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