Serum microRNA-21 as a potential biomarker for response to hypomethylating agents in myelodysplastic syndromes

Yundeok Kim, June-Won Cheong, Yeo-Kyeoung Kim, Ju-In Eom, Hoi-Kyung Jeung, Soo Jeong Kim, Dohyu Hwang, Jin Seok Kim, Hyeuong Joon Kim, Yoo Hong Min, Yundeok Kim, June-Won Cheong, Yeo-Kyeoung Kim, Ju-In Eom, Hoi-Kyung Jeung, Soo Jeong Kim, Dohyu Hwang, Jin Seok Kim, Hyeuong Joon Kim, Yoo Hong Min

Abstract

Identification of biomarkers that predict responses to hypomethylating agents (HMAs) will allow optimal strategies for epigenetic therapy in myelodysplastic syndromes (MDS) to be established. Serum miR-21 was quantitatively measured in 58 MDS patients treated with HMAs and 14 healthy controls. Serum miR-192 was an internal control, and diagnostic performance was evaluated according to receiver operating characteristics (ROCs). ROC analysis indicated that serum miR-21 levels differentiated responders from non-responders with an area under the curve of 0.648 (95% confidence, 0.49 to 0.72). The baseline level of serum miR-21 was significantly lower in the responder group than in the non-responder group (P = 0.041). The overall response rate (ORR) of the high miR-21 group was significantly lower than that of the low miR-21 group (41.2 vs. 73.2%, P = 0.021). Progression-free survival (PFS) was significantly inferior in the high group versus the low group (14.0 vs. 44.5 months, P = 0.001). Multivariate analyses revealed that the initial serum miR-21 level (P = 0.001) and circulating blasts (P = 0.007) were prognostic factors for PFS. Serum miR-21 level was significantly associated with ORR and PFS in MDS patients treated with HMAs. Although validation with a large prospective study is required, serum miR-21 is a potential biomarker of epigenetic therapy in MDS patients.

Conflict of interest statement

Competing Interests: The authors report that no competing interests exist.

Figures

Figure 1. Expression and stability of reference…
Figure 1. Expression and stability of reference gene candidates in the sera of healthy donors and patients with MDS.
(A) Quantification (Ct) of candidate reference miRNAs (miR-192, miR-16, and miR-93) in serum samples of healthy donors and MDS patients corrected for efficiency and two interpolate controls are shown. Box plots represent lower and upper quartiles with the median depicted with a horizontal line. Whiskers depict the 10th and 90th percentiles. Differences in serum levels of candidate miRNAs were not found between healthy donors (white box), MDS patients prior to HMA therapy (gray box), and MDS patients treated with four courses of HMA therapy (black box). (B) Average expression stability values for candidate reference miRs in MDS patients, which were calculated by the geNorm algorithm, are shown as a bar graph and with actual values. High expression stability is indicated by a low stability value. MDS, myelodysplastic syndromes; miRNAs, microRNAs; HMA, hypomethylating agents.
Figure 2. Differences in baseline serum miR-21…
Figure 2. Differences in baseline serum miR-21 expression levels.
(A) Difference in serum miR-21 levels between healthy donors and patients with MDS prior to HMA therapy. Expression levels of serum miR-21 were normalized to the reference gene, miR-192, which was selected as described in Design and Methods. (B) Difference in baseline serum miR-21 levels between responders to HMA therapy and non-responders. Bar graph and whisker indicate the median value and standard deviation of serum miR-21 levels, respectively. Significance is indicated by the P value.
Figure 3. Receiver operating characteristics (ROCs) curve…
Figure 3. Receiver operating characteristics (ROCs) curve analysis for the diagnostic value of miR-21.
The area under the ROC curve (AUC) was 0.648 (95% CI: 0.49 to 0.72).
Figure 4. Kaplan-Meier curves for overall survival…
Figure 4. Kaplan-Meier curves for overall survival and progression-free survival comparisons.
(A) Overall survival and (B) progression-free survival according to baseline serum miR-21 levels in patients with myelodysplastic syndromes treated with hypomethylating agents.

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