Sputum microRNA Biomarkers for Identifying Lung Cancer in Indeterminate Solitary Pulmonary Nodules

Abstract

Purpose The early detection of lung cancer in heavy smokers by low-dose CT (LDCT) can reduce the mortality. However, LDCT screening increases the number of indeterminate solitary pulmonary nodules (SPNs) in asymptomatic individuals, leading to overdiagnosis. Making a definitive preoperative diagnosis of malignant SPNs has been a clinical challenge. We have demonstrated that sputum miRNAs could provide potential biomarkers for lung cancer. Here we aimed to develop sputum miRNA biomarkers for diagnosis of malignant SPNs. Experimental Design Using quantitative reverse transcriptase PCR, we evaluated expressions of 13 sputum miRNAs, previously identified sputum miRNA signatures of lung cancer, in a training set of 122 patients with either malignant (n=60) or benign SPNs (n=62) to define a panel of biomarkers. We then validated the biomarker panel in an internal testing set of 136 patients with either malignant (n=67) or benign SPNs (n=69), and an external testing cohort of 155 patients with either malignant (n=76) or benign SPNs (n=79). Results In the training set, a panel of three miRNA biomarkers (miRs-21, 31, and 210) was developed, producing 82.93% sensitivity and 87.84% specificity for identifying malignant SPNs. The sensitivity and specificity of the biomarkers in the two independent testing cohorts were 82.09% and 88.41%, 80.52% and 86.08%, respectively, confirming the diagnostic value. Conclusions Sputum miRNA biomarkers may improve LDCT screening for lung cancer in heavy smokers by preoperatively diagnosing malignant SPNs. Nevertheless, a prospective study in a large population to validate the biomarkers is needed.

MicroRNA Expression Profiling of Sputum for the Detection of Early and Locally Advanced Non-Small-Cell Lung Cancer: A Prospective Case–Control Study

“…Xing et al 43 used a 3-mirna panel (mir-21, mir-31, mir-210) to evaluate sputum, yielding a sensitivity of 80.52% and a specificity of 86.08%. The mounting body of literature highlights the exciting potential of a noninvasive tool of this kind in nsclc diagnosis.…”

Non-coding RNAs: the cancer genome dark matter that matters!

“…The diagnostic value of microRNA expression in other body fluids for cancer detection has also been explored. Using Sputum samples, Xing et al showed that a panel of miR-21, miR-31, and miR-210 is able to differentiate malignant and benign solitary pulmonary nodules, with both high sensitivity and specificity (> 80%), in all three cohorts of samples [83]. Hanke et al reported that the ratio of miR-126 to miR-152, and the ratio of miR-182 to miR-152 are indicators of presence of bladder cancer [84].…”

Future microfluidic and nanofluidic modular platforms for nucleic acid liquid biopsy in precision medicine

“…[8][9][10][11][12][13][14][15][16][17][50][51][52][53][54][55] Reliable quantification of mRNA and microRNA levels for diagnostic and prognostic purposes requires optimal RNA quality and quantity. However, the different instances along the RNA and miRNA analysis workflow can lead to length, sequence, and structure-specific biases in the final expression analysis of a given set of small RNAs.…”

“…Equipment and analysis costs, throughput, and normalization 6,7 still represent obstacles for large-scale nucleic acid biomarker validation [8][9][10][11][12][13][14] and adoption in the clinics [15][16][17] Differences in the nucleic acid purification method, detection technology, and laboratory protocol often lead to different profiling results. Consequently, interpretation of differential expression data and comparisons across different studies has to be done with a note of caution, as standard deviations can span several orders of magnitude.…”