BackgroundMutations in KRAS and NRAS often result in constitutive activation of RAS in the epidermal growth factor receptor (EGFR) signaling pathway. Mutations in KRAS exon 2 (codon 12–13) predict resistance to anti-EGFR targeted therapy in patients with metastatic colorectal carcinoma (mCRC). However, it's currently known that a significant proportion of mCRC have RAS mutations outside KRAS exon 2, particularly in exons 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS. No data about RAS mutations outside KRAS exon 2 are available for Tunisian mCRC. The aim of this study was to analyze RAS, using pyrosequencing, in nine hotspots mutations in Tunisian patients with mCRC.MethodsA series of 131 mCRC was enrolled. Nine hotspots sites mutations of KRAS and NRAS were analyzed (KRAS: codons 12–13, codons 59–61, codon 117 and codon 146, NRAS: codons 12–13, codon 59, codon 61, codon 117 and codon 146) using Therascreen KRAS and RAS extension pyrosequencing kits.ResultsAnalysis was successful in 129 cases (98.5%). Mutations were observed in 97 cases (75.2%) dominated by those in KRAS exon 2 (86.6%). KRAS G12V was the most dominated mutation, observed in 25 cases (25.8%), and followed by KRAS G12S and KRAS G12D, each in 17 cases (17.5%). Mutations outside of KRAS exon 2 presented 13.4% of mutated cases and almost a third (28.8%) of KRAS exon 2 wild type mCRC. Among those, 9 cases (69.3%) carried mutations in NRAS exons 2, 3 and 4 and 4 cases (30.7%) in KRAS exons 3 and 4.ConclusionsRAS mutations outside exon 2 of KRAS should be included in routine practice, since they predict also response to anti-EGFR. That would make certain these patients benefit from appropriate testing and treatment. In addition unjustified expenses of anti-EGFR targeted therapy could be avoided.

IL23/IL17 pathway plays an important role in the development of inflammatory bowel diseases (IBD). In general, the genes encoding the cytokines are genetically polymorphic and polymorphisms in genes IL23R and IL17 have been proved to be associated with its susceptibility to inflammatory diseases as well as cancer including colorectal cancer. Moreover, it has been shown that these interleukins are involved in anti-tumor or pro-tumor effects of various cancers. Previously, we showed that there is a significant association between IL17A, IL17F and IL23R polymorphisms as well as the occurrence of colorectal cancer and the clinical features of the disease. The purpose of the present work is to investigate an association between IL17A, IL17F and IL23R polymorphisms in 102 Tunisian patients with colorectal cancer treatment. The association was analyzed by statistical tools. We found that patients with mutated genotypes of IL17A G197A SNP could be a risk factor for the inefficiency of chemotherapy and radiotherapy. Unlike IL17F variant, patients with wild type genotypes require surgery and adjuvant chemotherapy. On the one hand, we found no evidence that supports a significant association between IL23R polymorphism and the combined genotypes of these three genes and the colorectal cancer treatment. On the other hand, we showed that there is an important interaction between IL17A/IL17F polymorphisms and the stage of the disease as well as its treatment. Finally, patients with IL17F wild type genotype highlighted that there is a valid longer OS without all treatments and with radiotherapy and a neoadjuvant chemotherapy. In contrast, we observed that there are no relationships between IL17A, IL23R and the survival of these patients neither with nor without the treatment. Our results suggest that polymorphisms in IL17A and IL17F genes may be a predictive source of colorectal cancer therapy type. Therefore, IL17F may serve as an independent prognostic factor for overall survival in patients with colorectal cancer.