Journal of Experimental & Clinical Cancer Research | Abstract | Circulating microRNAs in cancer: origin, function and application

Journal of Experimental & Clinical Cancer Research | Abstract | Circulating microRNAs in cancer: origin, function and application

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

  Review

Circulating microRNAs in cancer: origin, function and application

Journal of Experimental & Clinical Cancer Research 2012, 31:38 doi:10.1186/1756-9966-31-38


Published: 30 April 2012

Abstract (provisional)

MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level. The dysregulation of miRNAs has been linked to a series of diseases, including various types of cancer. Since their discovery in the circulation of cancer patients, there has been a steady increase in the study of circulating miRNAs as stable, non-invasive biomarkers. However, the origin and function of circulating miRNAs has not been systematically elucidated. In this review, we summarize the discovery of circulating miRNAs and their potential as biomarkers. We further emphasize their possible origin and function. Finally, we discuss the application and existing questions surrounding circulating miRNAs in cancer diagnostics. Although several challenges remain to be concerned, circulating miRNAs could be useful, non-invasive biomarkers for cancer diagnosis.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production. 

Biomarkers in the circulation

"Circulating biomarkers undoubtedly play an increasingly significant role in clinicalapplications such as disease diagnostics, monitoring therapeutic effect and predicting recurrence in cancer patients. The currently used fluid-based biomarkers are primarily proteins, such as alpha-fetoprotein (AFP) [8], chromogranin A (CgA) [9], nuclear matrix
protein 22 (NMP 22) [10], carbohydrate antigen 125 (CA 125) [11]; enzymes, such as prostate specific antigen (PSA) [12]; and human chorionic gonadotropin (hCG) [13]. While these biomarkers provide an opportunity to analyze tumors comprehensively in an invasive
way, low sensitivity and specificity limit their clinical application. For example, serum levels of AFP are often elevated in hepatocellular carcinoma (HCC); however, this is also the case in germ cell tumors, gastric, biliary and pancreatic cancers.......

 reference/cited (google):

23. Resnick KE, Alder H, Hagan JP, Richardson DL, Croce CM, Cohn DE: The detection of differentially expressed microRNAs from the serum of ovarian cancer patients using a novel real-time PCR platform. Gynecol Oncol 2009, 112:55–59. 

 

open access: PLoS ONE: March 29th Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

PLoS ONE: Integrated Analyses of microRNAs Demonstrate Their Widespread Influence on Gene Expression in High-Grade Serous Ovarian Carcinoma

Background

The Cancer Genome Atlas (TCGA) Network recently comprehensively catalogued the molecular aberrations in 487 high-grade serous ovarian cancers, with much remaining to be elucidated regarding the microRNAs (miRNAs). Here, using TCGA ovarian data, we surveyed the miRNAs, in the context of their predicted gene targets.

Conclusions

This study establishes miRNAs as having a widespread impact on gene expression programs in ovarian cancer, further strengthening our understanding of miRNA biology as it applies to human cancer. As with gene transcripts, miRNAs exhibit high diversity reflecting the genomic heterogeneity within a clinically homogeneous disease population. Putative miRNA:mRNA interactions, as identified using integrative analysis, can be validated. TCGA data are a valuable resource for the identification of novel tumor suppressive miRNAs in ovarian as well as other cancers.

France: Search for Predictors of Therapeutic Response in Ovarian Carcinoma - Full Text View - ClinicalTrials.gov

Search for Predictors of Therapeutic Response in Ovarian Carcinoma (miRSa)

This study is currently recruiting participants.

Verified February 2012 by Centre Francois Baclesse

First Received on July 8, 2011. Last Updated on February 23, 2012 History of Changes

Further study details as provided by Centre Francois Baclesse:

Primary Outcome Measures:

• search for predictors of response to chemotherapy [ Time Frame: 12 months after beginning treatment ] [ Designated as safety issue: No ]
  the search for predictors of response to chemotherapy in patients with carcinoma of the ovary, the fallopian tube or peritoneal serous-type advanced by using (i) the miRNA profile of serum before treatment with chemotherapy and (ii) the identification of polymorphisms or SNPs (Single Nucleotide polymorphism) in particular genes involved in the metabolism of chemotherapy agents
  
  

Secondary Outcome Measures:

• profiling miRNA expression [ Time Frame: 1 month ] [ Designated as safety issue: No ]
  - Characterization of the response to treatment with profiling miRNA expression after the first course of chemotherapy in patients with carcinoma of the ovary, the fallopian tube or peritoneal serous-type advanced
  
  
• study of changes in serum miRNA expression [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  - The study of changes in serum miRNA expression identified as predictive of tumor response during chemotherapy treatment.

 

abstract: Blood Cell Origin of Circulating MicroRNAs: A Cautionary Note for Cancer Biomarker Studies

Abstract

Circulating, cell-free microRNAs (miRNAs) hold great promise as a new class of cancer biomarkers due to their surprisingly high stability in plasma, association with disease states, and ease of sensitive measurement. Yet little is known about the origin of circulating miRNAs in either healthy or sick people or what factors influence levels of circulating miRNA biomarkers. Of 79 solid tumor circulating miRNA biomarkers reported in the literature, we found that 58% (46 of 79) are highly expressed in one or more blood cell type. Plasma levels of miRNA biomarkers expressed by myeloid (e.g., miR-223, miR-197, miR-574-3p, and let-7a) and lymphoid (e.g., miR-150) blood cells tightly correlated with corresponding white blood cell counts. Plasma miRNA biomarkers expressed by red blood cells (e.g., miR-486-5p, miR-451, miR-92a, and miR-16) could not be correlated to red cell counts due to limited variation in hematocrit in the cohort studied but were significantly increased in hemolyzed specimens (20- to 30-fold plasma increase; P < 0.0000001). 

Finally, in a patient undergoing autologous hematopoietic cell transplantation, plasma levels of myeloid- and lymphoid-expressed miRNAs (miR-223 and miR-150, respectively) tracked closely with changes in corresponding blood counts. We present evidence that blood cells are a major contributor to circulating miRNA and that perturbations in blood cell counts and hemolysis can alter plasma miRNA biomarker levels by up to 50-fold.  

Given that a majority of reported circulating miRNA cancer biomarkers are highly expressed in blood cells, we suggest caution in interpretation of such results as they may reflect a blood cell-based phenomenon rather than a cancer-specific origin. Cancer Prev Res; 5(3); 1–6. ©2011 AACR.

full free access: Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer: A Systems Approach (technical/in research)

"Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basis of these complexities in cancer cells before the therapeutic potential of miRNAs can be fully realized."

abstract: DICER1 Mutations in Familial Multinodular Goiter (thyroid) With and Without Ovarian Sertoli-Leydig Cell Tumors

define: 

multinodular goiter - A multinodular goiter is  a thyroid gland that is usually enlarged and contains multiple thyroid nodules.

Pleuropulmonary blastoma (PPB) is a rare cancer originating in the lung or pleural cavity....
en.wikipedia.org/wiki/Pleuropulmonary_blastoma

 

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Objective To determine whether familial MNG  (multinodular goiter) with or without SLCT (Sertoli-Leydig cell tumor of the ovary) in the absence of PPB (pleuropulmonary blastoma)  was associated with mutations in DICER1. 

 

Conclusions DICER1 mutations are associated with both familial MNG and MNG with SLCT, independent of PPB. These germline DICER1 mutations are associated with dysregulation of miRNA expression patterns.

abstract: A microRNA survival signature (MiSS) for advanced ovarian cancer (serous)

 Abstract

Objectives

MicroRNAs (miRNAs) are a class of small non-coding RNAs that negatively regulate gene expression primarily through post-transcriptional modification. We tested the hypothesis that miRNA expression is associated with overall survival in advanced ovarian cancer.

Results

Of all patients, 80% had high-grade, stage IIIC tumors and 64% underwent optimal cytoreduction. The median survival for the entire cohort was 49 ± 4 months. The training set identified 3 miRNAs associated with survival — miR-337, miR-410, and miR-645. An miRNA signature containing miR-410 and miR-645 was most strongly associated with overall survival in the training set (HR = 2.96, 95% CI: 1.51–5.78). This miRNA survival signature (MiSS) was validated in the test set (HR = 1.71, 95% CI: 1.05–2.78). The MiSS was independent of FIGO stage and surgical debulking.

Conclusions

The data suggest that an MiSS that contains miR-410 and miR-645 is negatively associated with overall survival in advanced serous ovarian cancer. This signature, when further validated, may be useful in individualizing care for the ovarian cancer patient. Pathway analyses identify biologically plausible mechanisms.

Research highlights

► A MicroRNA Survival Signature was developed in advanced ovarian carcinoma.
► The signature was independent of common clinical co-variates.

abstract : Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening : British Journal of Cancer

Conclusion:

Our proof-of-principle study strengthens the hypothesis that neoplastic diseases generate characteristic miRNA fingerprints in blood cells. Still, the obtained OvCA-associated miRNA pattern is not yet sensitive and specific enough to permit the monitoring of disease progression or even preventive screening. Microarray-based miRNA profiling from peripheral blood could thus be combined with other markers to improve the notoriously difficult but important screening for OvCA.