Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population

Abstract

The MUTYH gene encodes a DNA glycosylase that can initiate the base excision repair pathway and prevent G:C > > > > T:A transversion by excising adenine mispaired with 8-hydroxyguanine. Biallelic germline mutations of MUTYH have been shown to predict familial and sporadic multiple colorectal adenomas and carcinomas, however, whether there is an association between single nucleotide polymorphisms (SNPs) of MUTYH and sporadic colorectal cancer (CRC) risk has remained unclear. In this study we investigated four MUTYH SNPs, I ntracellular DNA is at risk of damage by reactive oxygen species (ROS) generated by normal metabolism and environmental exposure, and 8-hydroxyguanine (8-ohG) is one of the products induced by ROS damage and is known to be a mutagenic lesion.(1,2) The base excision repair (BER) pathway plays an important role in repairing oxidative-damage-induced mutations, and the MUTYH gene encodes the glycosylase capable of initiating the BER pathway by catalyzing the removal of adenine residues mispaired with 8-ohG.(3-5) It has been indicated that defects in the BER pathway may contribute to tumorigenesis by increasing mutation frequency in oncogenes and tumor suppressor genes.(6) In fact, it has been reported that some cases of autosomal recessive inherited multiple colorectal adenomatous polyposis and carcinoma with an increased frequency of somatic G:C > T:A mutations in APC are attributable to biallelic germline mutations in the MUTYH gene.(7-10) The disease-causing mutations, Y165C, G382D, 466delE, E466X, and Y90X have been reported in Caucasians, Indian, Pakistani and other ethnic groups. (8,9,11,12) The frequencies of Y165C and G382D have been investigated in several colorectal cancer (CRC) case-control studies, and monoallelic carriers of these variants were found in 0.0 -2.6% of the cases and 0.0 -2.1% of the controls and biallelic carriers of these variants were found in 0.0-0.8% of the cases and 0% of the controls, respectively.(13-18) However, neither of these two variants has ever been detected in East Asians, including Japanese, (19)(20)(21)(22) suggesting that they are ethnicity-specific alleles. Based on the above findings, we hypothesized that MUTYH variants other than Y165C and G382D act as low-penetrance susceptibility alleles in Japanese CRC, similar to a situation previously reported for the APC and CHEK2 gene variants. (23,24) We conducted a CRC case-control study to evaluate the significance of MUTYH variants in a Japanese population. In the single-nucleotide polymorphisms (SNPs) reported in the Japanese population, (19,20) four SNPs (IVS1+11C > T, IVS6+35G > A, IVS10 -2A > G and 972G > C [Gln324His]), were selected, and all 685 cases and 778 matched controls were genotyped to detect these four SNPs. Statistically significant association was found between the IVS1+11C > T SNP and increased CRC risk in the Japanese population. A haplotye-based association study was also carried out, and a statistically significant association was found between the IVS1+11T -IVS6+35G -IVS10-2A -972C (TG...

Repair of 8-oxoG:A mismatches by the MUTYH glycosylase: Mechanism, metals and medicine

“…However, there have also been genetic studies that suggest an increased risk for CRC and lung cancer associated with the Q324H variant [139-142]. Analysis of the adenine glycosylase activity of Q324H MUTYH indicated a slightly reduced activity, similar to that observed with G382D MUTYH.…”

DNA repair genes polymorphisms and genetic susceptibility to Philadelphia-negative myeloproliferative neoplasms in a Portuguese population: The role of base excision repair genes polymorphisms

“…An example of one common SNP in the MUTYH gene is the nonsynonymous Gln335His variation in codon 12 (49,50). The enzyme encoded by this variant has been demonstrated to have partially impaired glycosylase activity in vitro , and could therefore contribute to cancer susceptibility, being much more frequently detected in Japanese and Chinese populations than in European populations (34,52). The Gln335His variant allele has been suggested to be associated with increased risk of colorectal cancer (50,52,57) and less consistently with lung cancer (53).…”

“…The enzyme encoded by this variant has been demonstrated to have partially impaired glycosylase activity in vitro , and could therefore contribute to cancer susceptibility, being much more frequently detected in Japanese and Chinese populations than in European populations (34,52). The Gln335His variant allele has been suggested to be associated with increased risk of colorectal cancer (50,52,57) and less consistently with lung cancer (53). For the latter, however, existing evidence is conflicting or significant only when taking into account gene-gene interactions (53).…”

Genes and SNPs Associated with Non-hereditary and Hereditary Colorectal Cancer

“…Mutations in this gene result in a heritable predisposition to colon and stomach cancers (Tsuzuki et al, 2007). Tao et al (2008) studied the association between genetic polymorphisms of MUTYH gene and increased CRC risk. They investigated four MUTYH SNPs, IVS1+11C>T, IVS6+35G>A, IVS10-2A>G, and 972G>C, for association with increased CRC risk in a population based series of 685 CRC patients and 778 control subjects from Kyushu, Japan.…”

“…This polymorphism occurs in the region between exon 1 and intron 1 of MUTYH gene. Also, to investigate the association of MUTYH G 13638 C and APEX1 T6865G with CRC and smoking in a Japanese population (Tao et al, 2008), Kasahara et al (2008) conducted a study. In this study the genetic polymorphisms of DNA repair enzymes MUTYH G 13638 C and APEX1 T6865G were determined using PCR-RFLP and results showed that the MUTYH G 13638 C is strongly associated with CRC susceptibility.…”