Abstract
BackgroundThe human MutY homolog (hMYH), a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC). We previously demonstrated a haplotype variant c.53C>T/c.74G>A of hMYH (T/A) increasing the risk for gastric cancer in Chinese. However, most investigations on correlation between hMYH and CRC are conducted in Western countries and the underlying mechanism has been poorly understood.MethodsTo 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.ResultsIt 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.ConclusionAlthough 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.
Highlights
The human MutY homolog, a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC)
Association analysis of the c.53C>T/c.74G>A variation with sporadic CRC An abnormal denaturing high-performance liquid chromatography (DHPLC) peak was found in exon 2 of human MutY homolog (hMYH) gene
The heterozygous frequencies of the hMYH mutation were detected at 4.35% in CRC group and 0.87% in control (Table 3), while no homozygote was found in the present study
Summary
The human MutY homolog (hMYH), a DNA glycolsylase involved in the excision repair of oxidative DNA damage, is currently studied in colorectal cancer (CRC). We previously demonstrated a haplotype variant c.53C>T/c.74G>A of hMYH (T/A) increasing the risk for gastric cancer in Chinese. It is recently discovered that the germline mutations of the human MutY homolog (hMYH) increase the susceptibility to develop colorectal cancers (CRC) associated with adenomatous polyposis [7,8]. The frequency of variant allele in suspected hereditary gastric cancer patients was significantly higher than that in the control group, which indicated that the T/A haplotype might form a partial genetic basis for the familial GC susceptibility in Chinese population. Kim et al [11] identified the germline haplotype T/A variation in patients with familial adenomatous polyposis (FAP) and showed tentative association with the development of FAP in Korean population
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