KRAS and NRAS pyrosequencing screening in Tunisian colorectal cancer patients in 2015

Abstract

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.

KRAS and NRAS Mutations in Moroccan Patients with Colorectal Cancer

“…The mean age of our patients was 55.41 and the most frequent age range was 51 to 64 years, these results were in agreement with Greater Casablanca cancer registry report 2012 and with Jouini et al findings in the Tunisian population [19,20]. The most tissue specimens were from primary tumors, a similar result was reported by Jouini, et al and Lee et al [20,21].The majority of our patients were diagnosed with adenocarcinoma, this result was similar to that reported by Lee et al and Rindi et al [8,21]. We did not find any correlation between the clinical parameters such as age, sex, stage of disease with RAS mutations, our results agreed with the observations of Most of the previous studies [21 -25].…”

Clinicopathological characteristics and mutational profile of KRAS and NRAS in Tunisian patients with sporadic colorectal cancer

“…We found that the most abundant mutations of codon were G12D and G12V while G13D is the predominant mutation in codon 13. These results are concordant with the local Tunisian studies [30,31,33,37] and the international ones [12,34,36,[38][39][40][41].…”

“…In our study, the NRAS mutation rate was 7.3%, similar to the only available Tunisian study which reported 6.9% [37].…”

“…Furthermore, Shen observed that these mutations were more frequent in distant metastasis tumors, and its rate varied with the different tumor stages [39]. Other studies did not find any correlations [29,36,37,49].…”

TP53 and NRAS are the Most Frequently Mutated Genes in Stool DNA of CRC Patients from Central Part of Iran

“…Data from 7 European countries showed that mutations in NRAS is predictors of lower response to anti-EGFR MoAbs treatment in CRC 31 . Jouini et al showed that NRAS gene mutated in 6.9% of the 129 Tunisian colorectal cancer specimens 32 . In Finnish stool DNAs, only one patient with rectum adenoma showed NRAS Q61R mutation 24 , while in another cohort of stool samples from Iranian CRC patients, none of them showed NRAS mutation in codon 12, 13 or 61 25 .…”