Stool- and Blood-Associated Colorectal Cancer Biomarkers: A Systematic Review

<b>Background/Objectives</b>: Colorectal cancer (CRC) is a major contributor to cancer-related deaths worldwide. While existing screening tools are effective, their high cost and limited availability restrict widespread adoption, particularly in low- and middle-income settings. The identification of affordable, non-invasive biomarkers is therefore critical to improve early CRC detection and survival outcomes. <b>Methods</b>: A systematic literature search was performed through PubMed, ScienceDirect, Medline, ISI Web of Knowledge, and Google Scholar to identify studies reporting stool- and blood-based biomarkers for CRC detection. Data were extracted using a standardized template, including study details, specimen type, detection method, and diagnostic performance parameters such as sensitivity and specificity. <b>Results</b>: DNA methylation biomarkers demonstrated high diagnostic potential. <i>Syndecan 2 (SDC2)</i> and <i>Short Stature Homeobox 2 (SHOX2)</i> achieved a combined stool sensitivity of 91.35%. Other methylation markers, including <i>NDRG4</i>, <i>SEPT9</i>, and <i>BCAT1</i>, showed a composite sensitivity of 82.7%. Plasma-based methylation markers such as <i>GATA5</i>, <i>FOXE1</i>, and <i>SYNE1</i> reported sensitivities ranging from 18-47% and specificities of 93-99%. Hypermethylation of <i>SFRP2</i> and <i>WIF-1</i> achieved 81.3% sensitivity in CRC and precursor lesions. <i>Matrix metalloproteinases</i> (<i>MMP-2</i> and <i>MMP-9</i>) were elevated in CRC patients, with stool <i>MMP-9</i> yielding 72.2% sensitivity and 95% specificity. A stool gene panel (<i>UBE2N</i>, <i>IMPDH1</i>, <i>DYNC1LI1</i>, <i>HRASLS2</i>) reached 96.6% sensitivity and 89.7% specificity, while a methylation-based panel (<i>ALX4</i>, <i>BMP3</i>, <i>NPTX2</i>, <i>RARB</i>, <i>SDC2</i>, <i>SEPT9</i>, <i>VIM</i>) achieved 90.7% sensitivity. MicroRNAs (<i>miR-21</i>, <i>miR-92a</i>, <i>miR-223</i>, <i>miR-182</i>) showed excellent diagnostic performance, with sensitivities exceeding 96% and specificities above 75%. <b>Conclusions</b>: DNA methylation and microRNA biomarkers hold strong promises for non-invasive CRC screening. Multi-marker panels demonstrate superior diagnostic accuracy and may provide a cost-effective, scalable approach for early CRC detection in resource-limited settings.