Systematic review and critique of circulating miRNAs as biomarkers of stage I-II non-small cell lung cancer

Abstract

Selected circulating microRNAs (miRNAs) have been suggested for non-invasive screening of non-small cell lung cancer (NSCLC), however the numerous proposed miRNA signatures are inconsistent.Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in serum/plasma samples, we searched the databases “Pubmed”, “Medline”, “Scopus”, “Embase” and “WOS” and systematically reviewed the publications reporting quantitative data on the efficacy [sensitivity, specificity and/or area under the curve (AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20 studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls, and were of medium quality according to Quality Assessment of Diagnostic Accuracy Studies checklist. In these studies, the patient cohorts as well as the control groups were heterogeneous for demographics and clinicopathological characteristics; moreover, numerous pre-analytical and analytical variables likely influenced miRNA determinations, and potential bias of hemolysis was often underestimated. We identified four circulating miRNAs scarcely influenced by hemolysis, each featuring high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step screening for stage I-II NSCLC using first the above panel of serum miRNAs with high sensitivity and high AUC, and subsequently the panel with high specificity, the estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and other circulating miRNAs suggested for stage I-II NSCLC screening require validation in multiple independent studies before they can be proposed for clinical application.

Circulating microRNA biomarkers for lung cancer detection in Western populations

“…Compared to previous reviews, we employed a broader inclusion criterion by including all histological types of LC cases, and we focused on studies conducted in Western populations in order to reduce a primary source of heterogeneity in miRNAs profiles. Although previous reviews have reported tremendous heterogeneity in included studies and inconsistency in LC‐related miRNA markers, very few reviews explored the sources of the heterogeneity . We comprehensively addressed heterogeneity from multiple perspectives, including study populations, biological sample types and processing, methodology in miRNA detection, and data normalization and analysis.…”

“…Our review suggests that circulating miRNAs have great potential to be used as markers for LC detection and may be promising candidates for general cancer screening. Compared to previous reviews, 39,[58][59][60][61][62][63][64][65] we employed a broader inclusion criterion by including all histological types of LC cases, and we focused on studies conducted in Western populations in order to reduce a primary source of heterogeneity in miRNAs profiles. Although previous reviews have reported tremendous heterogeneity in included studies and inconsistency in LC-related miRNA markers, very few reviews explored the sources of the heterogeneity.…”

“…Although previous reviews have reported tremendous heterogeneity in included studies and inconsistency in LC-related miRNA markers, very few reviews explored the sources of the heterogeneity. 62,65 We comprehensively addressed heterogeneity from multiple perspectives, including study populations, biological sample types and processing, methodology in miRNA detection, and data normalization and analysis. Thorough attention to those factors may help to standardize miRNA analytical procedures in the future.…”

Circulating microRNA‐590‐5p functions as a liquid biopsy marker in non‐small cell lung cancer

“…In lung cancer, low expression of the circulating miRNA‐34 family was associated with clinicopathological status and poor progression‐free and overall survival of NSCLC patients . miR‐223, miR‐20a, miR‐448, and miR‐145, as serum/plasma miRNA signatures, have shown high sensitivity (>80%), whereas another panel including miR‐628‐3p, miR‐29c, miR‐210, and miR‐1244 have shown high specificity (>90%) to stage I‐II NSCLC samples . Although several circulating miRNAs have been found to be associated with NSCLC, to date, their functional relevance in NSCLC has not been well characterized.…”

“…18 miR-223, miR-20a, miR-448, and miR-145, as serum/plasma miRNA signatures, have shown high sensitivity (>80%), whereas another panel including miR-628-3p, miR-29c, miR-210, and miR-1244 have shown high specificity (>90%) to stage I-II NSCLC samples. 19 Although several circulating miRNAs have been found to be associated with NSCLC, to date, their functional relevance in NSCLC has not been well characterized. Thus, a better understanding of the cellular functions of circulating miRNAs in NSCLC is warranted and may inform treatment responses.…”