Based on such information, the low prevalence of lymph node metastasis and p53 expression in our patients harboring the novel mutations coupled with the absence of EGFR and HER2 protein expression and EGFR gene mutations may generally suggest a low-grade pathway in colorectal cancer development in those patients, who are probably also resistant to R428 anti-EGFR and antiHER2 therapy. This speculation is in keeping with the finding that mutations in exon 4 of KRAS predict for a more favorable clinical outcome in patients with colorectal cancer. Ironically, four of the seven novel exon 4 mutations detected in the present study are predicted to be deleterious to the KRAS protein as revealed by molecular modeling. Moreover, only three out of the five patients harboring the deleterious mutations had more advanced disease with increased tumor depth and lymph node metastasis, while two had localized disease ! Could some of the mutations detected, alternatively, have a beneficial rather than a harmful effect on the host, possibly attributed to environmental factors? It has recently become clear that mutant RAS may result in highly divergent consequences in different tissues and environments. For example, overexpression of HRasV12 in immortalized mouse NIH3T3 cells causes transformation associated with activation of Raf and PI3K pathways, whereas overexpression of HRas in normal fibroblasts causes a senescent-like cell cycle arrest. Over expression of mutant RAS alleles results in a senescent-like phenotype that has been attributed to increased production of reactive oxygen species and associated stresses and is likely unrelated to the normal functions of single copy mutant RAS, which results in tumor initiation without senescence. It is to be noted that the two cases with concomitant exon 2 mutation showed greater tumor size and depth compared to most of the other cases and also had lymph node metastasis. The more extensive disease observed in those two cases may relate to the synergetic effect of the concomitant exon 2 mutation rather than a direct effect of the “deleterious” exon 4 mutations present. It is known that multiple mutations appear to be associated with a more aggressive disease. The seemingly contradictory observations described above may, however, be due to the small sample size studied. It remains, therefore, that further more advanced KRAS testing, including next generation sequencing, on a large number of patients, particularly beyond the most common hotspot alleles in exons 2 and 3 is needed to explore the exact prognostic and predictive significance of the discovered novel mutations as well as their possible role in colorectal carcinogenesis. Our discovery of novel Exon 4 KRAS mutations that are, so far, unique to Saudi patients from the Eastern Province may be attributed to environmental factors and/or genetic variation amongst different racial/ethnic groups. Alternatively, it may again be related to paucity of clinical studies on mutations other than those at codons 12, 13, 61 and 146 and could, in the future, prove to be more frequent and non-race restricted. The epidemiology of colorectal carcinoma in developing countries differs from that of developed countries.