Identification of Circulating MicroRNAs as a Promising Diagnostic Biomarker for Cervical Intraepithelial Neoplasia and Early Cancer: A Meta-Analysis

Abstract

Background. Cervical cancer (CC) is one of the most common female malignant tumors. And cervical intraepithelial neoplasia (CIN) is the precancerous lesion of CC, which can progress to invasive CC. MicroRNAs (miRNAs) have been found to be potential diagnostic biomarkers for CIN or CC. However, recently, the lack of sufficient studies about the diagnostic value of miRNAs for CIN made it challenging to separately investigate the diagnostic efficacy of miRNAs for CIN. Likewise, the conclusions among those studies were discordant. Therefore, we conducted this meta-analysis, aimed at evaluating the diagnostic efficacy of miRNAs for CIN and CC patients. Methods. Literature search was performed in PubMed, Embase, and Web of Science databases. Pooled sensitivity, specificity, and other diagnostic parameters were calculated through Stata 14.0 software. Furthermore, subgroup analyses and metaregression analysis were conducted to explore the main sources of heterogeneity. Results. Ten articles covering 50 studies were eligible, which included 5,908 patients and 4,819 healthy individuals. The pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.81 (95% CI, 0.77-0.85), 0.86 (95% CI, 0.83-0.89), 5.9 (95% CI, 4.5-7.7), 0.22 (95% CI, 0.17-0.28), 27 (95% CI, 17-44), and 0.91 (95% CI, 0.88-0.93), respectively. Additionally, the ethnicity and internal reference were the main sources of heterogeneity. Conclusions. Circulating miRNAs can be a promising noninvasive diagnostic biomarker for CIN and early CC, especially miR-9 and miR-205, which need to be verified by large-scale studies.

Novel biomarkers with promising benefits for diagnosis of cervical neoplasia: a systematic review

“…The high specificity ranges recorded from our review proved that miR-9 assay have diagnostic relevance to detect CIN2+. Although predictive values were missing in a number of studies included, sensitivity and specificity appeared to be similar across, and consistent with earlier review conducted by Jiang et al which recorded sensitivity, specificity, and AUC of 73, 94%, and 0.95, respectively, with 13.2 Positive Likelihood Ratio (PLR), and 0.28 Negative Likelihood Ratio (NLR) [53]. Experimental studies have shown that epigenetic instability is greatly influenced by miRNA which plays important role in transcriptional regulation, and any form of dysregulation as seen in overexpression often lead to a wide range of human malignancy including cervical cancer [2,3,11].…”

“…Like many other circulating miRNAs, studies have established that miR-9 could be useful for early detection of cervical cancer, predicting cancer prognosis, and in monitoring clinical outcome of cancer disease [55]. And that, by examining the associations between miR-9 levels in exfoliated cells, cervical tissues or serum; and the diverse biological processes such as metabolism and apoptosis, there is a consensus across studies showing that elevated levels is valuable for evaluating risk of cervical Intraepithelial neoplasia (CIN) in suspected individuals [2,7,53,55,57,58], especially in conjunction with other equally useful markers such as miR-21, miR-155, miR-192, miR-203 and miR-205 to improve specificity for optimal treatment benefit [2,11,48,53,[59][60][61]. Although our review is in agreement with this general consensus on diagnostic relevance of miR-9 in detection of CIN2+ [2,11], coupled with reduced turnaround time (TAT), and non-invasive blood sampling [53,55]; more robust clinical translation studies with larger consecutive cohorts of women participants would be appropriate for adequate validation alongside cost evaluation prior to implementation.…”

“…2). For miRNA (miR-9) assay, three studies recorded sensitivity, specificity and area under the ROC curve ranges of 52.9-67.3%, 76.4-94.4%%, and 0.71-0.85, respectively based on RT-qPCR platform using serum and tissue samples [2,11,53], with77.8% PPV and 70.2% NPV reported by Park et al [11]. 3) For the p16INK4a / ki-67 assays, twenty studies included reported sensitivity, specificity, PPV, NPV, and AUC ranges of 50-100%, 39-90.4%, 11.1-92.3%, 86.7-100%, and 0.76-0.90, respectively, based on immunocytochemistry (ICC) platform using liquid based cytology (LBC) samples [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] .…”

Human Papillomaviruses-Associated Cancers: An Update of Current Knowledge

“…On the other hand, it is difficult to find more than 4 of 187 studies reporting diagnostic accuracy for a particular miRNA (miR-20a and 205) or more than 2 reporting, albeit consistent, survival hazard ratios (miR-145, -34a, -205). Interestingly, a meta-analysis has indicated that circulating miR-205 was a good diagnostic biomarker [211].…”

Urine miRNA Signature as a Potential Non-invasive Diagnostic and Prognostic Biomarker in Cervical Cancer

“…and tumor suppressor miRNAs is proposed as a candidate biomarker in many cancers [9.10]. Apart from their detection in tumor tissues, several studies have also delineated the role of miRNAs derived from liquid biopsy samples, including plasma and serum, in cervical cancer [11][12][13][14].…”