**8. Summary**

514 DNA Repair

the persistence of 8-oxodG in genomic DNA in vivo, which, in turn, could be associated with

In 2003, Peng *et al.* (126) investigated the correlation among 8-oxodG levels, hOGG1 expression, and hOGG1 Cys326Ser polymorphism in Guangxi Autonomous Region. They found that individuals with genotypes with hOGG1 codon 326 Cys alleles faced lower level of hOGG1 expression and higher 8-oxodG levels. Supporting their results, Cheng *et al.* (21) reported that hOGG1 expression was significantly linear correlated with HCC. Recently, using the molecular epidemiological methods, Zhang *et al.*(127) found that the distribution of Cys alleles at codon 326 of hOGG1 in HCC cases (43.0%) significantly differed from in controls (33.1%). Logistic regression analysis showed that the genotypes with Cys alleles, compared to without this alleles, increased HCC risk of Chinese population, with adjusted OR-value (95% CI) 1.5 (0.79-2.93) for Cys/Ser and 1.9 (0.83-4.55) for Cys/Cys. These findings suggested pathogenic role of hOGG1 Cys326Ser polymorphism in the hepatocarcinogenesis.

**7. Genetic polymorphisms in genes involved in DSBR pathway and risk of** 

of AFB1-related HCC risk among Chinese population (58, 60).

China supported above-mentioned conclusions (58, 60).

DSBs, although only make up a very small proportion of AFB1-induced DNA damage, are critical lesions that can result in cell death or a wide variety of genetic alterations including large- or small-scale deletions, loss of heterozygosity, translocations, and chromosome loss (19, 128, 129). This type damage is repaired DSBR consisting of non-homologous end-joining (NHEJ) and homologous recombination (HR) (130-133). There are several decades DNA repair genes involves in DSBR pathway and the defects in these genes cause genome instability and promote tumorigenesis (128, 134, 135). In published molecular epidemiological studies, only XRCC3 gene codon Thr241Met polymorphism effects the risk

The product of the XRCC3 gene is one of identified paralogs of the strand-exchange protein RAD51 in human beings (136). This protein correlates directly with DNA breaks and facilitates of the formation of the RAD51 nucleoprotein filament, which is crucial both for homologous recombination and HRR (136-138). Previous studies have shown that a common polymorphism at codon 241 of XRCC3 gene (Thr to Met) modifies the function of this gene ad increases cancers risk (139-143). Two reports from high AFB1-exposure areas of

In the first frequent case-control study in Guangxiese (58), we observed that the genotypes with XRCC3 codon 241 Met alleles (namely Thr/Met and Met/Met) was significantly different between controls (33.01%) and HCC cases (61.48%, *P* < 0.001). Met alleles increases about 2- to 10-fold risk of HCC and this running-up risk is modulated by the number of Met alleles (adjusted OR 2.48 and 10.06 for one and two this alleles). Considering small sample size in this study, we recruited, in another independent frequent case-control study (60), a relatively larger sample size to compare the results. Subjects included in this study, 491 HCC cases and 862 age-, sex, race, hepatitis virus infection information-matching controls, were permanent residents of Guangxi areas. Similar to the results of the first report, the distribution of XRCC3 codon 241 Met allele frequency was found to be significantly different between cases (59.7%) and controls (32.1%). Individuals having the Thr/Met or Met/Met were at a 2.22-fold or 7.19 fold increased risk of developing HCC cancer. Above two studies showed this allele multiplicatively interacted with AFB1 exposure in the process

increased cancer risk (125, 126).

**HCC** 

Like most other human malignant tumors, HCC is a complex disease attributed to environment variation and genetic susceptive factors. In high incidence areas of HCC in China, AFB1 is an important environment variation as well as chronic HBV and HCV infection. This toxic variation is characterized by: *a.* the attraction of specific organs, especially liver; *b.* genotoxicity, mainly inducing the formation of AFB1-DNA adducts and the hot-spot mutation of p53 gene; and *c.* carcinogenicity, primarily causing HCC. In the process of AFB1 hepatocarcinogenesis, AFB1-DNA adducts play a central role because of their genotoxicity and interactions with genetic susceptive factors. Numerous studies reviewed in this paper have demonstrated that the hereditary variations in DNA repair genes are associated with susceptibility to AFB1-related HCC among Chinese population. These molecular epidemiological studies have significantly contributed to our knowledge of the importance of genetic polymorphisms in DNA repair genes in the etiology of HCC related to AFB1 exposure. It would be expected that genetic susceptibility factors involved in DNA repair genes for HCC could serve as useful biomarkers for identifying at-risk individuals and, therefore, targeting prevention of this malignant tumor.

However, there are several issues to be noted. Firstly, the conclusions should be drawn carefully, because of conflicting data existing in the same ethnic population in view of between some genotypes of DNA repair genes and the risk of HCC. Secondly, caution should be taken particularly in extrapolating these data to other ethnic populations, because of the difference of population frequencies corresponding to genetic polymorphisms that depends on ethnicity. Thirdly, when risk of a specific polymorphism is considered, AFB1 exposure should be stressed because AFB1 exposure may differ from areas to areas and from individuals to individuals. Lastly, because of the fact that AFB1-related hepatocarcinogenesis is polygenic, no single genetic marker may sufficiently predict HCC risk. Therefore, a panel of susceptive biomarkers is warranted to define individuals at highrisk for this cancer.
