The Study of KRAS Codon 12 and 13 Mutations and Their Relation to Risk of Colorectal Cancer in Isfahan

Saleh Jazi, Mohsen and Zahri, Saber and Latifi-Navid, Saeid and Talebi, Ardeshir (2017) The Study of KRAS Codon 12 and 13 Mutations and Their Relation to Risk of Colorectal Cancer in Isfahan. Masters thesis, University of Mohaghegh Ardabili.

Text (بررسی موتاسیون¬های کدون 12 و 13 ژن KRAS و ارتباط آن با خطر ابتلا به سرطان کولورکتال در اصفهان) Mohsen Saleh Jazi.pdf Download (1MB)

Abstract

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide and Iran. The KRAS mutations are found in 20% to 30% of cases. KRAS gene encodes 21 kDa protein (p21) that binds GDP and GTP and associated with the plasma membrane. Mutations in the KRAS gene induce the constitutive protein activity by eliminating the GTPase activity in the signal transduction pathway. Somatic mutations of KRAS are located up to 90% in codons 12 and 13 of exon 2. Therefore, this study evaluated the association of KRAS mutations with clinicopathologic features of CRC patients in Isfahan. This study was performed on 52 patients with CRC referred to the Al-Zahra hospital in Isfahan. The total DNA was extracted from fresh tumor and normal tissues. The exon 2 of KRAS gene was amplified and sequenced for detection of the point mutations. Using bioinformatics tools, sequence data analysis, structure prediction and pocket identification in KRAS protein conformation and also analysis of docking interactions were executed. All the mutation types and amino acid changes at the codon 12 and 13 were detected and the clinical and pathological associations of mutant genes were assessed. The prevalence of KRAS gene mutation was 15.4% (8 out of 52 cases). Six mutations found in codon 12(75%), were G12D and G12A types and two mutations in codon 13(25%) were only G13D. Common tumor sites were rectum and rectosigmoid. The mean age for patients was 61.2±13.9 years (range: 31-87 years). According to the results of the docking studies, KRAS G12D and G13D mutations may exhibit similar protein structure dynamics to WT KRAS. There was no significant relationship between the mutations and clinicopathologic features of CRC patients(p-value>0.05). This paper presents new results on the frequency of KRAS mutations in CRC patients. KRAS mutations could be used as molecular biomarker(s) to predict the lack of response to Anti-EGFR monoclonal antibodies. Key words: Anti-EGFR, Clinicopathologic, Codon 12 and 13, Colorectal cancer, Docking, KRAS, Mutation,

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