title: Novel KRAS gene mutations in sporadic colorectal cancer.
abstract: BACKGROUND
  In 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.
  
  
  METHODS
  Genomic 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.
  
  
  RESULTS
  KRAS 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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Molecular Diagnostics Lab, Department of Laboratory Medicine, King Fahd Hospital of the University, University of Dammam, Al-Khobar, Saudi Arabia.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Naser
authors.affiliation: Pathology Department, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Shawarby
authors.affiliation: Pathology Department, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Dalal M
authors.initials: DM
authors.lastname: Al-Tamimi
authors.affiliation: Molecular Diagnostics, Department of Anatomic Pathology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
authors.forename: Arun
authors.initials: A
authors.lastname: Seth
authors.affiliation: Department of Internal Medicine, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al-Quorain
authors.affiliation: Pathology Department, College of Medicine, University of Dammam, Dammam, Saudi Arabia.
authors.forename: Areej M Al
authors.initials: AM
authors.lastname: Nemer
authors.affiliation: Rheumatology Section, Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Omar M E
authors.initials: OM
authors.lastname: Albagha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D018389:Codon, Nonsense; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism; D005091:Exons; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D017434:Protein Structure, Tertiary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism; D012529:Saudi Arabia; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000737:chemistry / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D018631:ras Proteins; C512478:EGFR protein, human; C508053:ERBB2 protein, human