MUTYH is a base excision repair glycosylase responsible for correcting the G:A mismatches that arise from replication of a damaged DNA, such impairment results from attacks by reactive oxygen species that are produced from different sources including cigarette smoking. The produced reactive oxygen species trigger the oxidation of guanine in to 8-oxo-G and the latter mispairs with adenine. Alterations in the MUTYH gene can affect its glycosylase function and hence the DNA repair capacity that is tightly linked to cancer development. Defects in the MUTYH were found to be associated with predisposition to colorectal cancer; the third most common cancer in the world. Although some studies suggested the existence of an ethnic differentiation among MUTYH mutations, there are no documented reports regarding this gene in Saudi cases or controls so far. 153 healthy Saudi individuals including smokers were screened for the IVS1 + 5 G/C, V22M, Y165C, R231C, H324Q and G382D MUTYH variants using either ARMS or RFLP or direct sequencing. Allelic frequencies were calculated and were found to be as follows: IVS1 + 5 G/C = 1/0, V22M = 0.99/0.01, Y165C = 1/0, R231C = 1/0, H324Q = 0.29/0.71 and G382D = 0.997/0.003. Comparison of the allele frequencies between Saudis and other populations revealed a significant difference between the Saudis and Europeans for the V22M (p-value: 0.0003, OR: 5.899, 95% CI: 1.999 - 17.408); and between the Saudis and Asians for the H324Q (p-value: <0.0001, OR: 0.473, 95% CI: 0.341-0.6559). No significant differences were found between smokers and non-smokers groups. These data document the allele frequencies of different MUTYH variants in Saudi populations and support the existence of an ethnic difference between MUTYH variants which is beneficial as some MUTYH common polymorphisms in certain populations may correlate with disease predisposition in other rare populations.
nullShinwari, J. , Alamri, A. , Alanazi, M. and Tassan, N. (2011) Screening for variants in the MUTYH gene in Saudis. Open Journal of Genetics, 1, 70-77. doi: 10.4236/ojgen.2011.13013.
[1] De Bont, R. and van Larebeke, N. (2004) Endogenous DNA damage in humans: A review of quantitative data. Mutagenesis, 19, 169-185. doi:10.1093/mutage/geh025
[2] Lindahl, T. (1993) Instability and decay of the primary structure of DNA. Nature, 362, 709-715. doi:10.1038/362709a0
[3] Jackson, A.L. and Loeb, L.A. (2001) The contribution of endogenous sources of DNA damage to the multiple mutations in cancer. Mutation Research, 477, 7-21. doi:10.1016/S0027-5107(01)00091-4
[4] Nohmi, T., Kim, S.R. and Yamada, M. (2005) Modulation of oxidative mutagenesis and carcinogenesis by polymorphic forms of human DNA repair enzymes. Mutation Research, 591, 60-73. doi:10.1016/j.mrfmmm.2005.03.033
[5] Ohno, M., et al. (2006) A genome-wide distribution of 8- oxoguanine correlates with the preferred regions for recombination and single nucleotide polymorphism in the human genome. Genome Research, 16, 567-575. doi:10.1101/gr.4769606
[6] Slupska, M.M., et al. (1999) Functional expression of hMYH, a human homolog of the Escherichia coli MutY protein. Journal of Bacteriology, 181, 6210-6213.
[7] Ohtsubo, T., et al. (2000) Identification of human MutY homolog (hMYH) as a repair enzyme for 2-hydro-xyadenine in DNA and detection of multiple forms of hMYH located in nuclei and mitochondria. Nucleic Acids Research, 28, 1355-1364. doi:10.1093/nar/28.6.1355
[8] Shinmura, K., et al. (2000) Adenine excisional repair function of MYH protein on the adenine: 8-hydroxy-guanine base pair in double-stranded DNA. Nucleic Acids Research, 28, 4912-4918. doi:10.1093/nar/28.24.4912
[9] Tsuzuki, T., Nakatsu, Y. and Nakabeppu, Y. (2007) Significance of error-avoiding mechanisms for oxidative DNA damage in carcinogenesis. Cancer Science, 98, 465-470. doi:10.1111/j.1349-7006.2007.00409.x
[10] Michaels, M.L., et al. (1992) Evidence that MutY and MutM combine to prevent mutations by an oxidatively damaged form of guanine in DNA. Proceedings of the National Academy of Sciences of the USA, 89, 7022-7025. doi:10.1073/pnas.89.15.7022
[11] Charames, G.S. and Bapat, B. (2003) Genomic instability and cancer. Current Molecular Medicine, 3, 589-596. doi:10.2174/1566524033479456
[12] Al-Tassan, N., et al., Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nature Genetics, 30, 227-232. doi:10.1038/ng828
[13] Cheadle, J.P. and Sampson, J.R. (2007) MUTYH-associated polyposis from defect in base excision repair to clinical genetic testing. DNA Repair, 6, 274-279. doi:10.1016/j.dnarep.2006.11.001
[14] Enholm, S., et al. (2003) Proportion and phenotype of MYH-associated colorectal neoplasia in a population-based series of Finnish colorectal cancer patients. American Journal of Pathology, 163, 827-832. doi:10.1016/S0002-9440(10)63443-8
[15] Halford, S.E., et al. (2003) Germline mutations but not somatic changes at the MYH locus contribute to the pathogenesis of unselected colorectal cancers. American Journal of Pathology, 162, 1545-1548. doi:10.1016/S0002-9440(10)64288-5
[16] Jones, S., et al. (2002) Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. Human Molecular Genetics, 11, 2961-2967. doi:10.1093/hmg/11.23.2961
[17] Sampson, J.R., et al. (2003) Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet, 362, 39-41. doi:10.1016/S0140-6736(03)13805-6
[18] Sieber, O.M., et al. (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. The New England Journal of Medicine, 348, 791-799. doi:10.1056/NEJMoa025283
[19] Kambara, T., et al (2004) Role of inherited defects of MYH in the development of sporadic colorectal cancer. Genes Chromosomes Cancer, 40, 1-9. doi:10.1002/gcc.20011
[20] Yamaguchi, S., et al. (2002) A single nucleotide polymorphism at the splice donor site of the human MYH base excision repair genes results in reduced translation efficiency of its transcripts. Genes Cells, 7, 461-474. doi:10.1046/j.1365-2443.2002.00532.x
[21] Miyaki, M., et al. (2005) Germline mutations of the MYH gene in Japanese patients with multiple colorectal adenomas. Mutation Research, 578, 430-433. doi:10.1016/j.mrfmmm.2005.01.017
[22] Tao, H., et al. (2008) Association between genetic polymerphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population. Cancer Science, 99, 355-360. doi:10.1111/j.1349-7006.2007.00694.x
[23] Parker, A.R. and Eshleman, J.R. (2003) Human MutY: Gene structure, protein functions and interactions, and role in carcinogenesis. Cellular and Molecular Life Sciences, 60, 2064-2083. doi:10.1007/s00018-003-3053-4
[24] Nielsen, M., et al. (2007) Cost-utility analysis of genetic screening in families of patients with germline MUTYH mutations. BMC Medical Genetics, 8, 42. doi:10.1186/1471-2350-8-42
[25] Rahman, N. and Scott, R.H. (2007) Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players. Human Molecular Genetics, 16, 60-66. doi:10.1093/hmg/ddm026
[26] Sulova, M., et al. (2007) Mutation analysis of the MYH gene in unrelated Czech APC mutation-negative polyposis patients. European Journal of Cancer, 43, 1617- 1621. doi:10.1016/j.ejca.2007.04.010
[27] Shields, P.G. and Harris, C.C. (2000) Cancer risk and low-penetrance susceptibility genes in gene-environment interactions. Journal of Clinical Oncology, 18, 2309- 2315.
[28] Peterlongo, P., et al. (2005) Colorectal cancer risk in individuals with biallelic or monoallelic mutations of MYH. International Journal of Cancer, 114, 505-507. doi:10.1002/ijc.20767
[29] Boiteux, S. and Radicella, J.P. (2000) The human OGG1 gene: structure, functions, and its implication in the process of carcinogenesis. Archives of Biochemistry and Biophysics, 377, 1-8. doi:10.1006/abbi.2000.1773
[30] Nakabeppu, Y., et al. (2004) The defense mechanisms in mammalian cells against oxidative damage in nucleic acids and their involvement in the suppression of mutagenesis and cell death. Free Radical Research, 38, 423- 429. doi:10.1080/10715760410001688348
[31] Bruner, S.D., Norman, D.P. and Verdine, G.L. (2000) Structural basis for recognition and repair of the endogenous mutagen 8-oxoguanine in DNA. Nature, 403, 859- 866. doi:10.1038/35002510
[32] Shinmura, K. and Yokota, J. (2001) The OGG1 gene encodes a repair enzyme for oxidatively damaged DNA and is involved in human carcinogenesis. Antioxidants and Redox Signaling, 3, 597-609. doi:10.1089/15230860152542952
[33] Croitoru, M.E., et al. (2004) Association between biallelic and monoallelic germline MYH gene mutations and colorectal cancer risk. Journal of the National Cancer Institute, 96, 1631-1634. doi:10.1093/jnci/djh288
[34] Fleischmann, C., et al. (2004) Comprehensive analysis of the contribution of germline MYH variation to early-onset colorectal cancer. International Journal of Cancer, 109, 554-558. doi:10.1002/ijc.20020
[35] Kairupan, C.F., et al. (2005) Mutation analysis of the MYH gene in an Australian series of colorectal polyposis patients with or without germline APC mutations. International Journal of Cancer, 116, 73-77. doi:10.1002/ijc.20983
[36] Tao, H., et al. (2004) A novel splicesite variant of the base excision repair gene MYH is associated with production of an aberrant mRNA transcript encoding a truncated MYH protein not localized in the nucleus. Carcinogenesis, 25, 1859-1866. doi:10.1093/carcin/bgh206
[37] Zhang, Y., et al. (2006) Germline mutations and polymorphic variants in MMR, E-cadherin and MYH genes associated with familial gastric cancer in Jiangsu of China. International Journal of Cancer, 119, 2592-2596. doi:10.1002/ijc.22206
[38] Kim, I.J., et al. (2004) Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients. Human Genetics, 115, 498-503. doi:10.1007/s00439-004-1186-7
[39] Huang, M., et al. (2007) High-order interactions among genetic variants in DNA base excision repair pathway genes and smoking in bladder cancer susceptibility. Cancer Epidemiology, Biomarkers and Prevention, 16, 84-91. doi:10.1158/1055-9965.EPI-06-0712
[40] Miyaishi, A., et al. (2009) MUTYH Gln324His gene polymerphism and genetic susceptibility for lung cancer in a Japanese population. Journal of Experimental and Clinical Cancer Research, 28, 10. doi:10.1186/1756-9966-28-10