There have been significant developments in colon cancer research over the last few years, enabling us to better characterize tumors individually and classifying them according to certain molecular or genetic features. Currently, we are able to use KRAS mutational status as a guide to therapy with anti-epidermal growth factor receptor antibodies. Other molecular features under research include BRAF mutation, microsatellite instability, and CpG island methylation. These three molecular features are often associated with tumors that have overlapping phenotypes and can be present simultaneously in the same tumor. However, they carry different prognostic and predictive qualities, making analysis of their interaction relatively complex. Much research thus far has examined the clinical relevance of microsatellite instability in helping determine prognosis and the predictive value of adjuvant 5-fluorouracil chemotherapy in stages II and III colon cancers. BRAF mutation appears to be a biomarker for poor prognosis. CpG island methylation is tightly associated with microsatellite instable tumors and BRAF mutation, but its clinical utility remains uncertain. Hereby, we examine preclinical and clinical data that supports the utilization of all three phenotypes in future research applied to clinical practice. 1. Introduction Colorectal cancer (CRC) is the third most common cancer in the USA and the second leading cause of cancer death, with 141,210 annual new cases and 49,380 annual deaths in 2011 alone [1]. Survival for patients with CRC has improved dramatically over the last decade with the availability of 5-fluorouracil (5FU-) based doublet chemotherapy and the addition of molecularly targeted agents, such as, bevacizumab, cetuximab, and panitumumab in the metastatic setting [2–8]. Significant progress has been made in genotyping tumors and extracting clinically relevant information that may help guide us in early cancer detection, predictive biomarkers, and new target discovery. CpG island methylation phenotype (CIMP), microsatellite instability, and BRAF mutation may have clinical significance in colon cancer. These characteristics are due to genetic and epigenetic changes and have overlapping histopathological features that often occur in the same tumor. Their interaction is complex; for example, microsatellite instability-high (MSI) tumors carry a good prognosis whereas the presence of a BRAF mutation confers a poor outcome [9–15]. In this paper, we describe the clinical significance of CIMP, microsatellite instability, and BRAF mutation and their potential
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