Review ArticlesMolecular Pathology of Colorectal CancerHarada, Shuko MD; Morlote, Diana MDAuthor Information The University of Alabama at Birmingham, Birmingham, AL The authors have no funding or conflicts of interest to disclose. Reprints: Shuko Harada, MD, Department of Pathology, The University of Alabama at Birmingham, 1802 6th Avenue South, WP P210E, Birmingham, AL 35249 (e-mail: [email protected]). Advances In Anatomic Pathology: January 2020 - Volume 27 - Issue 1 - p 20-26 doi: 10.1097/PAP.0000000000000247 Buy Metrics Abstract Colorectal cancer (CRC) is the third most commonly diagnosed cancer. This review gives an overview of the current knowledge of molecular mechanisms of colorectal carcinogenesis and the role of molecular testing in the management of CRC. The majority of CRCs arise from precursor lesions such as adenoma, transforming to adenocarcinoma. Three molecular carcinogenesis pathways have been identified; (1) chromosomal instability, (2) microsatellite instability (MSI), and (3) CpG island methylator phenotype, each account for ~85%, 15%, and 17%, respectively. Evaluation of MSI status, extended RAS mutation analysis, and BRAF mutation analysis are recommended by the guideline published by joint effort from professional societies. MSI testing is important for identification of Lynch syndrome patients and prognostic and predictive markers. Extended RAS testing is an important predictive marker for antiepidermal growth factor receptor therapy. BRAF p.V600 mutation status can be used as prognostic marker, but not predictive marker for antiepidermal growth factor receptor therapies. Emerging technologies utilizing high throughput sequencing have introduced novel biomarkers and testing strategies. Tumor mutation burden predicts immunotherapy response in addition to MSI status. Liquid biopsy can be utilized when adequate tissue sample is not available or for monitoring therapy response. However, assay standardization and guidelines and recommendations for utilization of these assay will be needed. The advancement in CRC research and technologies will allow better prognostication and therapy stratification for the management of patients with CRCs. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.