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

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 ?l; 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.

SUBMITTER: Ono S

PROVIDER: S-EPMC4466669 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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

Ono Shigeshi S Oyama Takashi T Lam Stella S Chong Kelly K Foshag Leland J LJ Hoon Dave S B DS

Oncotarget 20150301 9

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 ...[more]

PMID: 25749524

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Project description:Primary cutaneous melanoma frequently metastasizes to distant organs including the brain. Identification of cell-free microRNAs (cfmiRs) found in the blood can be used as potential body fluid biomarkers for detecting and monitoring patients with melanoma brain metastasis (MBM). In this pilot study, we initially aimed to identify cfmiRs in the blood of MBM patients. Normal donors plasma (healthy, n = 48) and pre-operative MBM patients' plasma samples (n = 36) were compared for differences in >2000 microRNAs (miRs) using a next generation sequencing (NGS) probe-based assay. A 74 cfmiR signature was identified in an initial cohort of MBM plasma samples and then verified in a second cohort of MBM plasma samples (n = 24). Of these, only 58 cfmiRs were also detected in MBM tissues (n = 24). CfmiR signatures were also found in patients who have lung and breast cancer brain metastasis (n = 13) and glioblastomas (n = 36) compared to MBM plasma samples. The 74 cfmiR signature and the latter cfmiR signatures were then compared. We found a 6 cfmiR signature that was commonly upregulated in MBM plasma samples in all of the comparisons, and a 29 cfmiR signature that distinguishes MBM patients from normal donors' samples. In addition, we assessed for cfmiRs in plasma (n = 20) and urine (n = 14) samples collected from metastatic melanoma patients receiving checkpoint inhibitor immunotherapy (CII). Pre- and post-treatment samples showed consistent changes in cfmiRs. Analysis of pre- and post-treatment plasma samples showed 8 differentially expressed (DE) cfmiRs that overlapped with the 35 cfmiR signature found in MBM patients. In paired pre-treatment plasma and urine samples receiving CII 8 cfmiRs overlapped. This study identified specific cfmiRs in MBM plasma samples that may potentially allow for assessment of melanoma patients developing MBM. The cfmiR signatures identified in both blood and urine may have potential utility to assess CII responses after further validation.

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

Publications

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

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