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A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients.

Ono S, Oyama T, Lam S, Chong K, Foshag LJ, Hoon DS - Oncotarget (2015)

Bottom Line: In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012).Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001).We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.

ABSTRACT
Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 μl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

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Increase in cf-miR-210 level correlated with recurrence and poor prognosis(A) ROC analysis: Change in cf-miR-210 was a significant predictor of recurrence (cut off: one dCq difference; Sensitivity: 47.6%, Specificity: 91.3%. AUC = 0.623; p = 0.015). Positive: Recurrence < 2 yrs, Negative: No recurrence > 5 yrs. (B) Cf-miR-210 expression was significantly related to disease outcome (DFS, MSS: p < 0.001). Comparison of AJCC stage III melanoma patients with either > 1 dCq increase in cf-miR-210 levels from baseline to pre-treatment bleed (n = 24 patients) versus patients without such an increase (n = 64 patients). Blue line: No increase in cf-miR-210. Red line: Increase in cf-miR-210.
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Figure 5: Increase in cf-miR-210 level correlated with recurrence and poor prognosis(A) ROC analysis: Change in cf-miR-210 was a significant predictor of recurrence (cut off: one dCq difference; Sensitivity: 47.6%, Specificity: 91.3%. AUC = 0.623; p = 0.015). Positive: Recurrence < 2 yrs, Negative: No recurrence > 5 yrs. (B) Cf-miR-210 expression was significantly related to disease outcome (DFS, MSS: p < 0.001). Comparison of AJCC stage III melanoma patients with either > 1 dCq increase in cf-miR-210 levels from baseline to pre-treatment bleed (n = 24 patients) versus patients without such an increase (n = 64 patients). Blue line: No increase in cf-miR-210. Red line: Increase in cf-miR-210.

Mentions: In the patient cohort B, patients whose cf-miR-210 expression increased > 1 dCq from the baseline to their paired plasma were significantly more likely to recur. Receiver-operating characteristics (ROC) curve analysis was performed, and AUC was 0.623 (p = 0.015; Figure 5A). The Stage III patients with enhanced cf-miR-210 expression also experienced significantly poorer prognosis compared to patients whose cf-miR-210 expression did not significantly change. The differences in disease-free survival (DFS) and melanoma-specific survival (MSS) were highly significant (DFS: p < 0.001; MSS: p < 0.001; Figure 5B). An increase in cf-miR-210 expression in plasma was not associated with the adjuvant treatment type the patient received.


A direct plasma assay of circulating microRNA-210 of hypoxia can identify early systemic metastasis recurrence in melanoma patients.

Ono S, Oyama T, Lam S, Chong K, Foshag LJ, Hoon DS - Oncotarget (2015)

Increase in cf-miR-210 level correlated with recurrence and poor prognosis(A) ROC analysis: Change in cf-miR-210 was a significant predictor of recurrence (cut off: one dCq difference; Sensitivity: 47.6%, Specificity: 91.3%. AUC = 0.623; p = 0.015). Positive: Recurrence < 2 yrs, Negative: No recurrence > 5 yrs. (B) Cf-miR-210 expression was significantly related to disease outcome (DFS, MSS: p < 0.001). Comparison of AJCC stage III melanoma patients with either > 1 dCq increase in cf-miR-210 levels from baseline to pre-treatment bleed (n = 24 patients) versus patients without such an increase (n = 64 patients). Blue line: No increase in cf-miR-210. Red line: Increase in cf-miR-210.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466669&req=5

Figure 5: Increase in cf-miR-210 level correlated with recurrence and poor prognosis(A) ROC analysis: Change in cf-miR-210 was a significant predictor of recurrence (cut off: one dCq difference; Sensitivity: 47.6%, Specificity: 91.3%. AUC = 0.623; p = 0.015). Positive: Recurrence < 2 yrs, Negative: No recurrence > 5 yrs. (B) Cf-miR-210 expression was significantly related to disease outcome (DFS, MSS: p < 0.001). Comparison of AJCC stage III melanoma patients with either > 1 dCq increase in cf-miR-210 levels from baseline to pre-treatment bleed (n = 24 patients) versus patients without such an increase (n = 64 patients). Blue line: No increase in cf-miR-210. Red line: Increase in cf-miR-210.
Mentions: In the patient cohort B, patients whose cf-miR-210 expression increased > 1 dCq from the baseline to their paired plasma were significantly more likely to recur. Receiver-operating characteristics (ROC) curve analysis was performed, and AUC was 0.623 (p = 0.015; Figure 5A). The Stage III patients with enhanced cf-miR-210 expression also experienced significantly poorer prognosis compared to patients whose cf-miR-210 expression did not significantly change. The differences in disease-free survival (DFS) and melanoma-specific survival (MSS) were highly significant (DFS: p < 0.001; MSS: p < 0.001; Figure 5B). An increase in cf-miR-210 expression in plasma was not associated with the adjuvant treatment type the patient received.

Bottom Line: In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012).Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001).We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Oncology, John Wayne Cancer Institute, Providence Saint John's Health Center, Santa Monica, CA, USA.

ABSTRACT
Circulating cell-free(cf) microRNAs (miRNAs) have been reported to exist in plasma. MicroRNA-210(miR-210) is known to play important roles in the tumor hypoxic state. We hypothesized that the expression levels of cf-miR-210 in plasma would predict early clinical recurrence in melanoma patients. A direct miRNA assay on plasma (RT-qPCR-DP) was developed to improve cf-miRNA assay logistics, eliminate RNA extraction, and reduce specimen amount required. RNA was extracted from formalin-fixed paraffin-embedded (FFPE) melanoma tissues (n = 108) and assessed by RT-qPCR. Plasma (10 μl; n = 264) was procured from AJCC Stage III/IV patients in phase III clinical trials. A RT-qPCR-DP was performed to detect cf-miR-210. MiR-210 was significantly higher in metastatic tumors compared to primary tumors. Cf-miR-210 was significantly higher in melanoma patients versus healthy donor controls. In serial bloods within individual patients, cf-miR-210 < 3 months prior to disease recurrence significantly increased compared to baseline levels (p = 0.012). ROC curve analysis demonstrated that patients with elevated cf-miR-210 were more likely to have disease recurrence. Moreover, cf-miR-210 increase significantly correlated with poorer prognosis (p < 0.001). Lactate dehydrogenase (LDH) level was also assessed within patients, and the AIC values for proportional hazards regression models of cf-miR-210(120.01) and LDH (122.91) demonstrated that cf-miR-210 is a better recurrence indicator. We concluded enhanced cf-miR-210 provides identification of early systemic melanoma recurrence.

Show MeSH
Related in: MedlinePlus