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Currently, molecular testing in colorectal cancer (CRC) is aimed at detecting Lynch syndrome and predicting response to anti-epidermal growth factor receptor (EGFR) therapies. However, CRC is a complex disease, with at least 3 molecular pathways of carcinogenesis. The importance of the EGFR signaling pathway in colorectal carcinogenesis is underscored by the availability of anti-EGFR monoclonal antibodies for the treatment of some metastatic CRCs. Potentially, mutations in any of the genes in the EGFR signaling pathway may be associated with prognosis and may predict response to anti-EGFR or other targeted therapies. Although not currently the standard of care, molecular testing of CRCs is expanding to include mutational analysis of the genes in the EGFR pathway, in addition to more widely performed tests for identifying cancers with high microsatellite instability. Multiplex molecular prognostic panels for therapeutic decision making in stage II CRCs also represent expanding use of molecular testing for this common cancer.