Novel KRAS Gene Mutations in Sporadic Colorectal Cancer

Abstract

IntroductionIn this article, we report 7 novel KRAS gene mutations discovered while retrospectively studying the prevalence and pattern of KRAS mutations in cancerous tissue obtained from 56 Saudi sporadic colorectal cancer patients from the Eastern Province.MethodsGenomic DNA was extracted from formalin-fixed, paraffin-embedded cancerous and noncancerous colorectal tissues. Successful and specific PCR products were then bi-directionally sequenced to detect exon 4 mutations while Mutector II Detection Kits were used for identifying mutations in codons 12, 13 and 61. The functional impact of the novel mutations was assessed using bioinformatics tools and molecular modeling.ResultsKRAS gene mutations were detected in the cancer tissue of 24 cases (42.85%). Of these, 11 had exon 4 mutations (19.64%). They harbored 8 different mutations all of which except two altered the KRAS protein amino acid sequence and all except one were novel as revealed by COSMIC database. The detected novel mutations were found to be somatic. One mutation is predicted to be benign. The remaining mutations are predicted to cause substantial changes in the protein structure. Of these, the Q150X nonsense mutation is the second truncating mutation to be reported in colorectal cancer in the literature.ConclusionsOur discovery of novel exon 4 KRAS mutations that are, so far, unique to Saudi colorectal cancer patients may be attributed to environmental factors and/or racial/ethnic variations due to genetic differences. Alternatively, it may be related to paucity of clinical studies on mutations other than those in codons 12, 13, 61 and 146. Further KRAS testing on a large number of patients of various ethnicities, particularly beyond the most common hotspot alleles in exons 2 and 3 is needed to assess the prevalence and explore the exact prognostic and predictive significance of the discovered novel mutations as well as their possible role in colorectal carcinogenesis.

Driver Gene Mutations in Stools of Colorectal Carcinoma Patients Detected by Targeted Next-Generation Sequencing

“…Two other KRAS truncating mutations (in codons 22 and 150) have been reported in CRC in the literature. 31,32 In addition, eight of nine mutations in the FBXW7 gene were located at the WD repeat domain. This domain mediates interaction with substrates of the SCF E3 ubiquitin-protein ligase complex, which has important roles in the ubiquitination of proteins involved in cell division and growth.…”

Oncogenic Ras mutant causes the hyperactivation of NF‐κB via acceleration of its transcriptional activation

“…In CRC patients, 40% of patients’ samples harbored a point mutation of K‐Ras gene (Bos, ; Naser et al , ). Finally, we investigated whether oncogenic mutation of the K‐Ras gene in CRC causes phosphorylation of the p65/RelA subunit at Ser‐276.…”

Untangling the KRAS mutated lung cancer subsets and its therapeutic implications

“…This multiplexed single nucleotide probe extension assay detects point mutations from very small quantity of DNA [ 113 ]. These include; (i) EGFR mutations- c.2573 T > G (L858R), c.2369C > T (T790M); (ii) KRAS mutations- c.34G > T (p.Gly12Cys), c.35G > T (p.Gly12Val); (iii) PIK3CA mutations- c.1624G > A (E542K), c.1633G > A (E545K); (iv) BRAF mutation- c.1799 T > A (V600E).…”