Activating mutations in KRAS gene cause constitutively active Ras GTPase, which leads to over-activation of downstream Raf/Erk/Map kinase and other signaling pathways, resulting in cell transformation and tumorigenesis (Fig 1) (2),(3). KRAS mutations are present in approximately 30% to 50% of colon cancer specimens (4).

Fearon and Vogelstein established a stepwise hypothesis for colorectal cancer tumorigenesis and delineated the importance of mutation in Inhibitors,research,lifescience,medical RAS gene as an initiating event in the formation of malignant tumor (5). Rapamycin mw Figure 1 Epidermal growth factor receptor signal transduction pathway. * Common sites of mutation in colorectal cancer. Preclinical studies have suggested that constitutively activated mutant KRAS can promote tumor invasion and metastasis by stimulating matrix metalloproteases, cysteine proteases, serine proteases, and urokinase plasminogen activator that facilitate migration through the basement membrane (6),(7),(8). Despite such findings the Inhibitors,research,lifescience,medical role of KRAS mutation in prognosis of mCRC patients is not clear. The RASCAL study, which was the largest study designed to analyze the prognostic value

of KRAS status showed that a glycine-to-valine mutation in codon 12 increased the selleck catalog likelihood of disease relapse and a lower overall survival (OS) (9). Multiple other studies with smaller sample size did Inhibitors,research,lifescience,medical not demonstrate any impact

of KRAS mutations on survival (10),(11),(12). Even in the updated RASCAL II study, the evidence of a statistically significant worse clinical outcome was limited to stage III disease and was not confirmed for other stages (13). Inhibitors,research,lifescience,medical These results are limited by their retrospective nature and lack of adequate power to detect significant differences. The relationship between KRAS status of primary tumor and stage at diagnosis as well as pattern of spread is also not clear. Samowitz et al. reported that codon 12 mutations in KRAS gene were found to be much more common in proximal tumors and were associated Inhibitors,research,lifescience,medical with advance stage at presentation (14). Bazan and colleagues showed Batimastat that codon 12 mutation in tumor was associated with mucinous histology and mutation in codon 13 was associated with advanced Duke stage (15). In a retrospective study KRAS mutation of the primary tumor was also associated with higher incidence of metastatic disease to lungs (16). Analysis of KRAS and BRAF mutation status in PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer revealed that incidence of either mutation was not significantly different according to tumor stage. KRAS mutation was associated with grade of the tumor, while BRAF mutation was associated with right-sided tumors, older age, female gender, high grade, and MSI-high tumors.