title: High frequency of genes' promoter methylation, but lack of BRAF V600E mutation among Iranian colorectal cancer patients.
abstract: Gene silencing due to DNA hypermethylation is a major mechanism for loss of tumor suppressor genes function in colorectal cancer. Activating V600E mutation in BRAF gene has been linked with widespread methylation of CpG islands in sporadic colorectal cancers. The aim of the present study was to evaluate the methylation status of three cancer-related genes, APC2, p14ARF, and ECAD in colorectal carcinogenesis and their association with the mutational status of BRAF and KRAS among Iranian colorectal cancer patients. DNA from 110 unselected series of sporadic colorectal cancer patients was examined for BRAF V600E mutation by PCR-RFLP. Promoter methylation of genes in tumors was determined by methylation specific PCR. The frequency of APC2, E-CAD, and p14 methylation was 92.6%, 40.4% and 16.7%, respectively. But, no V600E mutation was identified in the BRAF gene in any sample. No association was found in cases showing epigenetic APC, ECAD, and p14 abnormality with the clinicopathological parameters under study. The association between KRAS mutations and the so called methylator phenotype was previously reported. Therefore, we also analyzed the association between the hot spot KRAS gene mutations in codons of 12 and 13 with genes' promoter hypermethylation in a subset of this group of patients. Out of 86 tumors, KRAS was mutated in 24 (28%) of tumors, the majority occurring in codon 12. KRAS mutations were not associated with genes' methylation in this tumor series. These findings suggest a distinct molecular pathway for methylation of APC2, p14, and ECAD genes from those previously described for colorectal cancers with BRAF or KRAS mutations.
authors: Department of Biochemistry, Shiraz University of Medical Sciences, School of Medicine, Zand Street, Shiraz, Fars, Iran. fakhraddin.naghibalhossaini@mail.mcgill.ca
authors: Fakhraddin
authors: F
authors: Naghibalhossaini
authors: Hamideh Mahmoodzadeh
authors: HM
authors: Hosseini
authors: Pooneh
authors: P
authors: Mokarram
authors: Mozhdeh
authors: M
authors: Zamani
mesh_terms: D015820:Cadherins / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D018899:CpG Islands; D003598:Cytoskeletal Proteins / Q000235:genetics; D019175:DNA Methylation; D057890:Epigenomics / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: C115681:APC2 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins