A haplotype variation affecting the mitochondrial transportation of hMYH protein could be a risk factor for colorectal cancer in Chinese

To determine whether the haplotype T/A variant of hMYH was related to colorectal carcinogenesis, we performed a case-control study in 138 colorectal cancer (CRC) patients and 343 healthy controls in a Chinese population. Furthermore, the C/G for wild-type, C/A or T/G for single base variant and T/A for haplotype variant hMYH cDNAs with a flag epitope tag were cloned into pcDNA3.1+ vector and transfected into cos-7 cell line. Their subcellular localizations were determined by immunofluorescence assay.It was found that the frequency of haplotype variant allele was statistically higher in CRC patients than that in controls (P = 0.02, odds ratio = 5.06, 95% confidence interval = 1.26 – 20.4). Similarly, significant difference of heterozygote frequency was indicated between the two groups (P = 0.019), while no homozygote was found. In addition, immunofluorescence analysis showed that hMYH protein with haplotype T/A variation presented in both nucleus and mitochondria, in contrast to the wild-type protein only converging in mitochondria. However, neither of the single missense mutations alone changed the protein subcelluar localization.Although preliminarily, these results suggest that: the haplotype variant allele of hMYH leads to a missense protein, which partly affects the protein mitochondrial transportation and results as nuclear localization. This observation might be responsible for the increased susceptibility to cancers, including CRC, in Chinese.Base excision repair (BER) is a major mechanism for the repair of DNA base damage by reactive oxygen species (ROS)[1]. The most stable product of oxidative DNA damage, 8-oxo-guanine (8-oxoG), tends to mispaire with adenine, which would lead to a transversion of G:C to T:A [2,3]. The MutY DNA glycosylase initiates the repair pathway by recognizing and removing the adenine misincorporated with 8-oxoG [4]. A series of biochemical studies demonstrate that the E. coli strain lacking MutY is a mutator for G:C to T:A transversi