Genetic prognostic and predictive markers in colorectal cancer

Key Points The most studied markers of colorectal cancer prognosis and response to therapy are somatic mutations in KRAS , adenomatous polyposis coli( APC ) and TP53 . With the exception of KRAS mutations and their association with clinical resistance to epidermal growth factor receptor (EGFR)-specific antibody therapy, there is no compelling evidence that these markers have a role in clinical decision making. Chromosomal instability is associated with a worse prognosis, and microsatellite instability with a better prognosis. Germline polymorphisms have been described in the metabolic pathways of chemotherapeutic agents used in colorectal cancer — for example, 5-fluorouracil (5-FU) and irinotecan — which correlate with the degree of toxicity. High-throughput expression and genotyping arrays are starting to generate novel markers and gene signatures that may be of use in the management of colorectal cancer. At present, these are not sufficiently validated to be clinically useful. Linking the collection of tissue and germline DNA to well-designed clinical trials will increase our understanding of the mechanisms of poor prognosis, and with it our capacity to identify novel biomarkers. New technologies have led to an explosive increase in the number of biomarkers thought to be associated with prognosis and treatment outcome in colorectal cancer. How effective are the biomarkers already in the public domain? Despite many studies of the likely survival outcome of individual patients with colorectal cancer, our knowledge of this subject remains poor. Until recently, we had virtually no understanding of individual responses to therapy, but the discovery of the KRAS mutation as a marker of probable failure of epidermal growth factor receptor (EGFR)-targeted therapy is a first step in the tailoring of treatment to the individual. With the application of molecular analyses, as well as the ability to perform high-throughput screens, there has been an explosive increase in the number of markers thought to be associated with prognosis and treatment outcome in this disease. In this Review, we attempt to summarize the sometimes confusing findings, and critically assess those markers already in the public domain.