Plasma MicroRNA Signature Validation for Early Detection of Colorectal Cancer

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer-related death worldwide and is expected to increase by 60% by 2030 (1). Although some strategies are available to screen average risk patients including fecal occult blood testing (FOBT) (immunochemical test) alone or combined with stool DNA examination, endoscopy (sigmoidoscopy or colonoscopy), and a blood-based test to evaluate biomarkers, each one of them have important disadvantages (2). Current fecal test has the advantages of cut-off that can be adjusted and low price whereas stool DNA test has shown to detect significantly more cancers than fecal test and better sensitivity for advanced adenomas (AA). By contrast, lower specificity demands more colonoscopy resources being invasive and costly. Sigmoidoscopy and colonoscopy offer direct visualization and detection of a colonic polyps or advanced neoplasia with the advantage of getting a pathology specimen. Only adequate biomarkers used in a screening setting will allow detecting precancerous adenomas (called AA) that could be removed during colonoscopy, reducing cancer incidence or also detecting malignant lesions at stages where cure is possible. To achieve higher levels of adherence to CRC screening, accurate blood-based test seems to be the best strategy (3). MicroRNAs (miRNAs) are 18–22 nucleotide noncoding RNAs that post-transcriptionally regulate gene expression and control various cellular mechanisms including tumorigenesis and the development of various types of cancers (4–6). Accumulating evidence supports the existence of specific miRNA in biological fluids that can facilitate earlier detection of the tumors becoming then diagnostic biomarkers. In particular, circulating miRNAs have also emerged as promising diagnostic biomarkers for CRC (5). For instance, several authors demonstrated that miR21 in serum is a promising biomarker for the early detection and prognosis of CRC (7,8). More recently, miR-200c and miR-203 implicated in epithelial-to-mesenchymal transition have been described as noninvasive biomarker for CRC prognosis and to predict metastasis (9,10). Fecal miR-106a was shown to be a useful maker for patients with CRC negative for immunochemical fecal test (11). Because some other publications reported different accuracy values when various miRNAs are used as biomarkers, reproducible and confirmatory studies are required to validate analytical and clinical robustness. In line with these innovative data, we demonstrated in a previous study (12) that patients with CRC and AA have significantly different patterns of miRNA expression than healthy individuals. A set of miRNAs (i.e., miRNA19a, miRNA19b, miRNA15b, miRNA29a, miRNA335, and miRNA18a) is upregulated, having discriminative capacity when found in plasma samples. We hypothesized that a specific signature of miRNA could be used for CRC screening purposes. Based on our previous work, our aim here was to design and validate a robust predictive model that can distinguish healthy individuals from those with advanced neoplasm (i.e., CRC or AA) in a larger cohort to confirm clinical validity.