Serum miR-223: A Validated Biomarker for Detection of Early-Stage Non–Small Cell Lung Cancer

Abstract

Background: The published circulating miRNA signatures proposed for early-stage non-small cell lung cancer (NSCLC) detection are inconsistent and difficult to replicate. Reproducibility and validation of an miRNA simple signature of NSCLC are prerequisites for translation to clinical application.Methods: The serum level of miR-223 and miR-29c, emerging from published studies, respectively, as a highly sensitive and a highly specific biomarker of early-stage NSCLC, was measured with droplet digital PCR (ddPCR) technique in an Italian cohort of 75 patients with stage I-II NSCLC and 111 tumor-free controls. By ROC curve analysis we evaluated the miR-223 and miR-29c performance in discerning NSCLC cases from healthy controls.Results: Reproducibility and robust measurability of the two miRNAs using ddPCR were documented. In a training set (40 stage I-II NSCLCs and 56 controls), miR-223 and miR-29c, respectively, showed an AUC of 0.753 [95% con-fidence interval (CI), 0.655-0.836] and 0.632 (95% CI, 0.527-0.729) in identifying NSCLC. Combination of miR-223 with miR-29c yielded an AUC of 0.750, not improved over that of miR-223 alone. Furthermore, in an independent blind set (35 stage I-II NSCLCs and 55 controls), we validated serum miR-223 as an effective biomarker of stage I-II NSCLC (AUC ¼ 0.808; 95% CI, 0.712-0.884), confirming the miR-223 diagnostic performance reported by others in Chinese cohorts. Conclusions: Using ddPCR technology, miR-223 was externally validated as a reproducible, effective serum biomarker of early-stage NSCLC in ethnically different subjects. Combination with miR-29c did not improve the miR-223 diagnostic performance.Impact: Serum miR-223 determination may be proposed as a tool for refining NSCLC risk stratification, independent of smoking habit and age.

MicroRNA‐223 in gastrointestinal cancers: A systematic review and diagnostic meta‐analysis

“…Yang et al 31 examined the role of serum miR‐223 in NSCLC diagnosis and the AUC was reported to be 0.740 (95% CI: 0.653‐0.816), while the sensitivity and specificity values were not reported. D'Antona et al 32 proposed new aspects of miR‐223 diagnostic performance in patients with NSCLC. In the mentioned study, the AUC was reported to be 0.808 (95% CI: 0.712‐0.884), the sensitivity was 74.3 (95% CI: 56.7‐87.5), and the specificity was 78.2 (95% CI: 65.0‐88.2) 32 …”

“…D'Antona et al 32 proposed new aspects of miR‐223 diagnostic performance in patients with NSCLC. In the mentioned study, the AUC was reported to be 0.808 (95% CI: 0.712‐0.884), the sensitivity was 74.3 (95% CI: 56.7‐87.5), and the specificity was 78.2 (95% CI: 65.0‐88.2) 32 …”

Measurements Methods for the Development of MicroRNA-Based Tests for Cancer Diagnosis

“…Duplicates also increase the sensitivity in detecting low abundance targets, as data from duplicates can be summed up, increasing the number of measured events. Digital PCR has been shown to have the potential for developing diagnostic and prognostic tests based on miRNA measurements [ 75 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. However, like qPCR, digital PCR needs miRNA extraction and reverse transcription and therefore some of the drawbacks of qPCR remain the same.…”

“…In 2019 miR-223 was validated as a reproducible, effective serum biomarker of early-stage non-small-cell lung cancer using ddPCR technology [ 75 ]. A recent study from Detassis and colleagues demonstrated that miR375-3p distinguishes low-grade neuroendocrine from non-neuroendocrine lung tumors in FFPE samples [ 76 ].…”

Noncoding RNAs and Liquid Biopsy in Lung Cancer: A Literature Review

“…However, these results, among those from other studies [120,121], need proper validation before they can prove their benefit. In a recent study, miR-223 has been validated as an effective and reproducible serum biomarker of early stage NSCLC by using digital-droplet PCR technology [122]. Li et al (2017) identified in a prospective study, using RT-qPCR on plasma samples from 71 patients (41 ALK-positive), a panel of three circulating miRNAs that can discriminate between patients diagnosed with ALK-positive and ALK-negative lung cancers.…”