Genetic prognostic and predictive markers in colorectal cancer

Abstract

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.