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.

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