The promise of personalized medicine is now a clinical reality, with colorectal cancer genetics at the forefront of this next major advance in clinical medicine. This is no more evident than in the testing of colorectal cancers for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor (EGFR).1, 2, 3
Indeed, the discovery that acquired KRAS
mutations are a robust predictive marker of resistance to cetuximab and panitumumab 4, 5
has led to clinically validated and cost-effective testing strategies to direct these drugs to appropriate patients. This discovery resulted from a detailed understanding of colorectal cancer genetics, including the role of KRAS
mutations in colorectal carcinogenesis, as well as knowledge of the epidermal growth factor (EGFR) signaling pathways.6
The success of KRAS
mutation testing in predicting treatment response is just the beginning of the use of genetic markers for directing the care of colorectal cancer patients. Many other genetic markers in colorectal cancer show promise for their use in treatment selection, prognosis, and early cancer detection. In this context, knowledge of the underlying genetic mechanisms of colorectal tumorigenesis and the potential of specific genetic lesions for clinical decision making is expected to become part of the working knowledge of care providers managing colon cancer patients. However, despite the promising advances in the molecular pathology of colorectal cancer that are highlighted in this review, it is important to emphasize that clinicopathological staging of tumor tissue is still the cornerstone of prognostication and treatment selection. The modern tumor-node-metastasis (TNM) classification system is recommended, although the original Dukes staging system is still used by some clinicians and is taught to pathologists in training.7
The pathologic features with greatest prognostic power are depth of tumor invasion, burden of lymphovascular invasion (estimated by the number of lymph nodes infiltrated by cancer), and presence of distant metastases. Efforts to correlate genetic alterations with histologic features have had limited success, although microsatellite instability is a molecular feature that shows modest correlation with certain histologic features such as cribriform architecture and medullary histology.8
Thus, molecular testing is usually required for accurate assessment of specific gene mutations or genomic instability that provide prognostic and predictive information beyond clinicopathologic features.
In this review, we examine genetic mechanisms of colorectal cancer and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers) (). The genetic features of colorectal cancer that are currently most clinically useful will be emphasized in this review, and a detailed description of the molecular genetics and molecular biology of the germane genetic and epigenetic alterations will be provided. We will conclude by reviewing the potential role for genetic markers in the selection of targeted colorectal cancer therapies that are in pre-clinical development or in Phase I and II trials.
Selected Biomarkers That Have Been Evaluated in Colorectal Cancer