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      Circulating miR-378 in plasma: a reliable, haemolysis-independent biomarker for colorectal cancer

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          Abstract

          Background:

          Plasma circulating tumour-specific microRNAs (miRNAs) are promising biomarkers of tumour presence and recurrence, especially for diseases whose best chance of successful treatment requires early diagnosis and timely surgery of an already malignant but not yet invasive tumour, such as colorectal cancer (CRC).

          Methods:

          Expression levels of miRNAs previously found to be differently expressed in tumour vs normal colon tissues were investigated by quantitative real-time PCR in plasma from CRC patients and from healthy donors and confirmed in independent case control series. The validated miRNAs were also measured after surgery. Analyses were repeated on the subsets of haemolysis-free samples.

          Results:

          We identified four miRNAs differently expressed between the compared groups, two (miR-21 and miR-378) of which were validated. miR-378 expression decreased in non-relapsed patients 4–6 months after surgery and miR-378 ability to discriminate CRC patients from healthy individuals was not influenced by haemolysis levels of plasma samples.

          Conclusion:

          The miRNA analysis on plasma samples represents a useful non-invasive tool to assess CRC presence as well as tumour-free status at follow-up. Plasma levels of miR-378 could be used to discriminate CRC patients from healthy individuals, irrespective of the level of haemoglobin of plasma samples.

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          Most cited references21

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          Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis.

          In the past several years, the importance of microRNA (miRNA) in cancer cells has been recognized. Proper control of miRNA expression is essential for maintaining a steady state of the cellular machinery. Recently, it was discovered that extracellular miRNAs circulate in the blood of both healthy and diseased patients, although ribonuclease is present in both plasma and serum. Most of the circulating miRNAs are included in lipid or lipoprotein complexes, such as apoptotic bodies, microvesicles, or exosomes, and are, therefore, highly stable. The existence of circulating miRNAs in the blood of cancer patients has raised the possibility that miRNAs may serve as a novel diagnostic marker. However, the secretory mechanism and biological function, as well as the meaning of the existence of extracellular miRNAs, remain largely unclear. In this review, we summarize the usefulness of circulating miRNA for cancer diagnosis, prognosis, and therapeutics. Furthermore, we propose a mechanism for the secretion and incorporation of miRNA into the cells. © 2010 Japanese Cancer Association.
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            Worldwide variations in colorectal cancer.

            Previous studies have documented significant international variations in colorectal cancer rates. However, these studies were limited because they were based on old data or examined only incidence or mortality data. In this article, the colorectal cancer burden and patterns worldwide are described using the most recently updated cancer incidence and mortality data available from the International Agency for Research on Cancer (IARC). The authors provide 5-year (1998-2002), age-standardized colorectal cancer incidence rates for select cancer registries in IARC's Cancer Incidence in Five Continents, and trends in age-standardized death rates by single calendar year for select countries in the World Health Organization mortality database. In addition, available information regarding worldwide colorectal cancer screening initiatives are presented. The highest colorectal cancer incidence rates in 1998-2002 were observed in registries from North America, Oceania, and Europe, including Eastern European countries. These high rates are most likely the result of increases in risk factors associated with "Westernization," such as obesity and physical inactivity. In contrast, the lowest colorectal cancer incidence rates were observed from registries in Asia, Africa, and South America. Colorectal cancer mortality rates have declined in many longstanding as well as newly economically developed countries; however, they continue to increase in some low-resource countries of South America and Eastern Europe. Various screening options for colorectal cancer are available and further international consideration of targeted screening programs and/or recommendations could help alleviate the burden of colorectal cancer worldwide.
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              Plasma microRNAs are promising novel biomarkers for early detection of colorectal cancer.

              MicroRNA (miRNA) opens up a new field for molecular diagnosis of cancer. However, the role of circulating miRNAs in plasma/serum in cancer diagnosis is not clear. The aim of this study was to investigate whether plasma miRNAs can be used as biomarkers for the early detection of colorectal carcinoma (CRC). We measured the levels of 12 miRNAs (miR-134, -146a, -17-3p, -181d, -191, -221, -222, -223, -25, -29a, -320a and -92a) in plasma samples from patients with advanced colorectal neoplasia (carcinomas and advanced adenomas) and healthy controls using real-time RT-PCR. We found that plasma miR-29a and miR-92a have significant diagnostic value for advanced neoplasia. MiR-29a yielded an AUC (the areas under the ROC curve) of 0.844 and miR-92a yielded an AUC of 0.838 in discriminating CRC from controls. More importantly, these 2 miRNAs also could discriminate advanced adenomas from controls and yielded an AUC of 0.769 for miR-29a and 0.749 for miR-92a. Combined ROC analyses using these 2 miRNAs revealed an elevated AUC of 0.883 with 83.0% sensitivity and 84.7% specificity in discriminating CRC, and AUC of 0.773 with 73.0% sensitivity and 79.7% specificity in discriminating advanced adenomas. Collectively, these data suggest that plasma miR-29a and miR-92a have strong potential as novel noninvasive biomarkers for early detection of CRC.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                18 February 2014
                14 January 2014
                : 110
                : 4
                : 1001-1007
                Affiliations
                [1 ]Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                [2 ]Molecular Genetics of Cancer, Fondazione Istituto FIRC di Oncologia Molecolare , via Adamello 16, 20139 Milano, Italy
                [3 ]Unit of Medical Statistics Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                [4 ]Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                [5 ]Transfusion Medicine Service, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                [6 ]Colorectal Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                [7 ]Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori , via G. Venezian 1, 20133 Milano, Italy
                Author notes
                [8]

                These authors contributed equally to this work.

                [9]

                These authors contributed equally to this work as co-last authors.

                Article
                bjc2013819
                10.1038/bjc.2013.819
                3929896
                24423916
                1be47bbb-f2b2-4e4f-ae45-2bbae1c7ebf2
                Copyright © 2014 Cancer Research UK

                From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 03 September 2013
                : 04 December 2013
                : 10 December 2013
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                colorectal cancer,plasma,tumour-related circulating mirna,early diagnosis,tumour recurrence,haemolysis free

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