Second leading cause of cancer deaths in the United States [2]. 15900046 Recently developed therapies have significantly improved patient survival even after metastasis development. Despite these improvements in chemotherapy for metastatic colorectal cancer (mCRC), the overall five-year survival rate remains poor at only 11 for patients with metastatic disease [1]. Anti-epidermal growth factor receptor (anti-EGFR) therapies, involving cetuximab (ErbituxH, ImClone Systems) and panitumumab (VectibixH, Amgen) have been approved by the US Food andDrug Administration (FDA) for the Title Loaded From File treatment of mCRC in the refractory disease setting [3,4]. These monoclonal antibodies, chimeric and humanized, bind to the EGFR, preventing activation of the EGFR downstream signaling pathways, which are important for cancer cell proliferation, invasion, metastasis, and neo-vascularization [5]. One important member of this pathway is KRAS, and the evidence of anti-EGFR therapies improving the clinical benefits of wild-type (WT) KRAS in mCRC patients is well known and established [6,7]. The KRAS gene encodes the KRAS protein that contains 188 amino acid residues with a molecular mass of 21.6kD [8]. KRAS is a membrane-associated GTPase thatComputational Analysis of KRAS Mutationsis an early player in many signal transduction pathways. KRAS acts as a molecular on/off switch to recruit and activate the proteins necessary for the propagation of the growth factor and other receptor signals, such as c-Raf and PI 3-kinase. When Title Loaded From File activated, KRAS is involved in the dephosphorylation of GTP to GDP, after which KRAS is turned off. However, the issue of whether patients harboring KRAS mutations can benefit from the addition of cetuximab or panitumumab to standard chemotherapy is under debate. Currently, health authorities in the United States and Europe have indicated that patients with KRAS-mutated tumors should not receive cetuximab or panitumumab. Consequently, only KRAS WT patients are treated with anti-EGFR therapies. KRAS mutations are reported in approximately 40 ?0 of all colorectal cancer specimens [9,10]. These mutations principally occur in codons 12 and 13 and less frequently in codons 61, 63, and 146. Population-based studies have suggested that these mutations might be associated with some tumor phenotypes [11,12]. Interestingly, recent study [13] indicated that the frequency of KRAS mutation was highest in caecal cancers among all 18325633 subsites. The same group also proposed that luminal contents, including gut microbial communities and their metabolites, might trigger initiating molecular events or, alternatively, influence the tumour microenvironment and promote neoplastic progression [14]. When all these mutations are taken together, approximately 80 of patients have mutations in codon 12 whereas 18 have mutations in codon 13 [15]. Mutations in codons 61 and 146 have also been found to be oncogenic in KRAS, although these mutations occur at much lower prevalence (,5 of total KRAS mutations) than codon 12 and 13 mutations [16]. Mutations in codons 12 and 13 leads to alterations in encoded amino acids adjacent to the GDP/GTP binding pocket, reducing or abolishing the GTPase activity of KRAS after guanine nucleotide activating protein (GAP) binding and locking the protein in an active, GTPbound state [17]. Both codons 12 and 13 in KRAS WT encode the glycine residues. The incorporation of other amino acids, most commonly aspartate and valine at codon 12 and aspartate at co.Second leading cause of cancer deaths in the United States [2]. 15900046 Recently developed therapies have significantly improved patient survival even after metastasis development. Despite these improvements in chemotherapy for metastatic colorectal cancer (mCRC), the overall five-year survival rate remains poor at only 11 for patients with metastatic disease [1]. Anti-epidermal growth factor receptor (anti-EGFR) therapies, involving cetuximab (ErbituxH, ImClone Systems) and panitumumab (VectibixH, Amgen) have been approved by the US Food andDrug Administration (FDA) for the treatment of mCRC in the refractory disease setting [3,4]. These monoclonal antibodies, chimeric and humanized, bind to the EGFR, preventing activation of the EGFR downstream signaling pathways, which are important for cancer cell proliferation, invasion, metastasis, and neo-vascularization [5]. One important member of this pathway is KRAS, and the evidence of anti-EGFR therapies improving the clinical benefits of wild-type (WT) KRAS in mCRC patients is well known and established [6,7]. The KRAS gene encodes the KRAS protein that contains 188 amino acid residues with a molecular mass of 21.6kD [8]. KRAS is a membrane-associated GTPase thatComputational Analysis of KRAS Mutationsis an early player in many signal transduction pathways. KRAS acts as a molecular on/off switch to recruit and activate the proteins necessary for the propagation of the growth factor and other receptor signals, such as c-Raf and PI 3-kinase. When activated, KRAS is involved in the dephosphorylation of GTP to GDP, after which KRAS is turned off. However, the issue of whether patients harboring KRAS mutations can benefit from the addition of cetuximab or panitumumab to standard chemotherapy is under debate. Currently, health authorities in the United States and Europe have indicated that patients with KRAS-mutated tumors should not receive cetuximab or panitumumab. Consequently, only KRAS WT patients are treated with anti-EGFR therapies. KRAS mutations are reported in approximately 40 ?0 of all colorectal cancer specimens [9,10]. These mutations principally occur in codons 12 and 13 and less frequently in codons 61, 63, and 146. Population-based studies have suggested that these mutations might be associated with some tumor phenotypes [11,12]. Interestingly, recent study [13] indicated that the frequency of KRAS mutation was highest in caecal cancers among all 18325633 subsites. The same group also proposed that luminal contents, including gut microbial communities and their metabolites, might trigger initiating molecular events or, alternatively, influence the tumour microenvironment and promote neoplastic progression [14]. When all these mutations are taken together, approximately 80 of patients have mutations in codon 12 whereas 18 have mutations in codon 13 [15]. Mutations in codons 61 and 146 have also been found to be oncogenic in KRAS, although these mutations occur at much lower prevalence (,5 of total KRAS mutations) than codon 12 and 13 mutations [16]. Mutations in codons 12 and 13 leads to alterations in encoded amino acids adjacent to the GDP/GTP binding pocket, reducing or abolishing the GTPase activity of KRAS after guanine nucleotide activating protein (GAP) binding and locking the protein in an active, GTPbound state [17]. Both codons 12 and 13 in KRAS WT encode the glycine residues. The incorporation of other amino acids, most commonly aspartate and valine at codon 12 and aspartate at co.
