Fecal microRNAs, Fecal microRNA Panels, or Combinations of Fecal microRNAs with Fecal Hemoglobin for Early Detection of Colorectal Cancer and Its Precursors: A Systematic Review

SIMPLE SUMMARY: Screening for colorectal cancer is effective for the reduction of both CRC incidence and mortality in the population at average risk. The use of innovative and robust biomarkers to enhance the potential of noninvasive CRC screening remains desirable. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. Several studies have reported quite promising results, in particular by combining fecal miRNA measurements with fecal hemoglobin. However, current evidence is limited by substantial heterogeneity in the methodology from study design to biosample analysis. Our review is intended to provide a valuable reference for future biomarker studies in early colorectal cancer detection. Looking at fecal miRNAs, we draw attention to the various biases to be avoided or at least minimized, by applying a harmonized methodology including true screening settings and comparable sample pre-analytics, as well as the validation of biomarkers. ABSTRACT: Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer mortality globally. Fecal miRNAs have been suggested to be promising biomarkers for CRC early detection. We aimed to conduct a systematic literature review on the diagnostic performance of fecal miRNA markers for CRC and its precursors. PubMed and Web of Science were searched to retrieve relevant articles published up to 7 December 2021. Information on study design, characteristics of study population, pre-analytics (sample collection, processing, and storage), fecal miRNA extraction and quantification technologies, and diagnostic performance (including sensitivity, specificity, and area under the curve (AUC)) were summarized. Twenty studies reporting on 31 individual miRNAs and 16 miRNA panels (with 2–9 markers) for CRC diagnosis were identified. Substantial heterogeneity existed regarding stool sample collection, processing, storage, and miRNA extraction and normalization. For two individual miRNAs and one miRNA panel, values ≥ 80% were reported for both sensitivity and specificity; however, none of these results were either internally or externally validated. In a study among fecal immunochemical test-positive cases recruited from a true screening setting, better diagnostic performance was identified and internally validated for a combination panel including two miRNAs, fecal hemoglobin level, and patient age and sex, compared with fecal hemoglobin concentration alone. Fecal miRNAs or miRNA panels, possibly in combination with fecal hemoglobin test, may be promising candidates for noninvasive CRC early detection. However, large prospective and well-designed studies in CRC screening cohorts are required to validate promising miRNAs or miRNA panels.