Serum microRNA Biomarkers for Detection of Non-Small Cell Lung Cancer

Abstract

Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73–0.91), sensitivity of 100% (95% CI; 0.93–1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results.

Lung Cancer Detection by Screening - Presenting Circulating miRNAs as a Promising Next Generation Biomarker Breakthrough

“…The results prove that specific miRNA signatures in pre-disease plasma samples can predict and discriminate the development of more aggressive disease, like in early metastatic tumours that can be frequently be undetectable by yearly spiral CT surveillance. The highlight of the study was number of deregulated miRNAs decreases with increasing time distance to diagnosis which is against the idea that extended time of sample storage can alter miRNA pattern (Hennessey et al, 2012).…”

miRNAs as Biomarkers and Therapeutic Targets in Non-Small Cell Lung Cancer: Current Perspectives

“…A negative result was found in 810 out of the 1067 (76%) individuals without lung cancer and in 10 of the 48 (21%) individuals with lung cancer, and the authors suggested that the miRNA test could be used as a first-line screening tool in high-risk individuals. However, the usefulness of miRNAs extends beyond the early detection of NSCLC [89,90]. miRNA panels offer the possibility to differentiate NSCLC from benign lesions and to determine the histological tumour type from a tissue sample [87,91], with sensitivities and specificities within the range of 60-100%.…”

Genetically Engineered Mouse Models for Human Lung Cancer

“…Several miRNA pairs involving miRNAs-106a, miR-15b, miR-27b, miR-142-3p, miR-26b, miR-182, 126#, let7g, let-7i (described above) and miR-30e-5p exhibited a negative predictive value and a positive predictive value of 100%. Notably, a combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy volunteers with high sensitivity, specificity (Hennessey et al, 2012). Upon further testing on additional 130 subjects, this miRNA pair predicted NSCLC with a specificity of 84%, sensitivity of 100%.…”

“…These studies indicate that knocking-down of miR-21 expression in cancer cells results in phenotypes important for tumor biology. Hennessey et al (2012) conducted Phase I/II biomarker study to examine the feasibility of using serum miRNA as biomarkers for NSCLC. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs.…”