Association study between polymorphisms of XRCC1, hOGG1 in DNA repair gene and the risk of endometrial carcinoma: a meta-analysis

Objective The association of DNA repair gene XRCC1, hOGG1 polymorphisms with susceptibility to endometrial carcinoma (EC) have been extensively studied with inconsistent results. The objective of this study was to clarify this issue by a comprehensive review and meta-analysis. Methods English (PubMed, Medline, Embase) and Chinese (CNKI, wanfang) electric databases were searched to collect a case-control study on the association between XRCC1 or hOGG1 gene polymorphisms and endometrial carcinoma. The retrieval time was from the database until may 1th, 2019. According to inclusion and exclusion criteria, relevant data of the final included literature were extracted and STATA 11.0 software was used for meta analysis. Results A total of 8 references meeting the inclusion criteria were included for analysis from the 243 retrieved literatures. The Arg399Gln polymorphism at the XRCC1 gene was associated with increased susceptibility to endometrial carcinoma (OR=1.36, 95%CI=1.23~1.51, P<0.001) in the overall population, the same results were shown in the subgroup analysis of Caucasians (OR=1.44, 95%CI=1.29~1.61, P<0.001). Ser326Cys polymorphism of the hOGG1 gene also increases the risk of endometrial carcinoma in Caucasians (OR=1.54, 95%CI=1.34~1.76, P=0.001). No publication bias was detected in this meta-analysis. Conclusions This meta-analysis provided evidence that the Arg399Gln polymorphism of DNA repair gene XRCC1 may increase risk of endometrial carcinoma, especially in the Caucasian. Moreover, Ser326Cys polymorphism of hOGG1 increase endometrial carcinoma risk in the Caucasian.

Impact of polymorphisms in DNA repair genes XPD, hOGG1 and XRCC4 on colorectal cancer risk in a Chinese Han Population

Background: This research aimed to study the associations between XPD (G751A, rs13181), hOGG1 (C326G, rs1052133) and XRCC4 (G1394T, rs6869366) gene polymorphisms and the risk of colorectal cancer (CRC) in a Chinese Han population. Method: A total of 225 Chinese Han patients with CRC were selected as the study group, and 200 healthy subjects were recruited as the control group. The polymorphisms of XPD G751A, hOGG1 C326G and XRCC4 G1394T loci were detected by the RFLP-PCR technique in the peripheral blood of all subjects. Results: Compared with individuals carrying the XPD751 GG allele, the A allele carriers (GA/AA) had a significantly increased risk of CRC (adjusted OR = 2.109, 95%CI = 1.352–3.287, P=0.003). Similarly, the G allele (CG/GG) of hOGG1 C326G locus conferred increased susceptibility to CRC (adjusted OR = 2.654, 95%CI = 1.915–3.685, P<0.001). In addition, the T allele carriers (GT/TT) of the XRCC4 G1394T locus have an increased risk of developing CRC (adjusted OR = 4.512, 95%CI = 2.785–7.402, P<0.001). The risk of CRC was significantly increased in individuals with both the XPD locus A allele and the hOGG1 locus G allele (adjusted OR = 1.543, 95%CI = 1.302–2.542, P=0.002). Furthermore, individuals with both the hOGG1 locus G allele and the XRCC4 locus T allele were predisposed to CRC development (adjusted OR = 3.854, 95%CI = 1.924–7.123, P<0.001). The risks of CRC in XPD gene A allele carriers (GA/AA) (adjusted OR = 1.570, 95%CI = 1.201–1.976, P=0.001), hOGG1 gene G allele carriers (CG/GG) (adjusted OR = 3.031, 95%CI = 2.184–4.225, P<0.001) and XRCC4 gene T allele carriers (GT/TT) (adjusted OR = 2.793, 95%CI = 2.235–3.222, P<0.001) were significantly higher in patients who smoked ≥16 packs/year. Conclusion: Our results suggest that XPD G751A, hOGG1 C326G and XRCC4 G1394T gene polymorphisms might play an important role in colorectal carcinogenesis and increase the risk of developing CRC in the Chinese Han population. The interaction between smoking and these gene polymorphisms would increase the risk of CRC.

Increased Mitochondrial Gene Deletions and ROS Production in Transgenic Mice Overexpressing a Human 8-Oxoguanine DNA-Glycosylase Gene: A Causal Association with the Development of Hematopoietic Neoplasms

Alterations of nuclear genes in human diseases including neoplasms have been well investigated in past several decades and unequivocally established their predominant role in the pathogenesis. However, the relationship of mitochondrial genome alteration with human diseases remains largely unknown. Mitochondria are dynamic organelles involved in oxidative phosphorylation and production of reactive oxygen species (ROS). Accumulated evidence supports that mitochondrial DNA damage and dysfunction play vital roles in the development of a wide array of mitochondria-related human diseases, such as obesity, diabetes, infertility, neurodegenerative disorders and malignant tumors. We previously described the development of a transgenic (TG) mouse model for mitochondrial DNA damage by overexpressing human mitochondrial isoform of 8-oxoguanine DNA Glycosylase 1 (hOGG1) gene. Over-expression of this gene produced a wide range of adverse biological phenotypes, manifesting early-onset obesity, metabolic disturbance, female infertility, high frequency of B-cell lymphoma and human essential thrombocythemia like myeloproliferative disorder, involving the lymph node, bone marrow, spleen, liver and other extranodal sites. Development of these hematopoietic neoplasms appeared to be age-dependent. In the current study, we focused on the pathogenesis of the hematopoietic neoplasms by characterization of the neoplasms via pathologic, biochemical and molecular approaches. While expression of mOGG1 was very similar in parallel organs from transgenic and wild-type control mice, the hOGG1 TG mice expressed very high levels of human OGG1 transgene mRNA, being 6.8- and 112-fold as high as the endogenous mouse OGG, in the spleen and bone marrow. By contrast, hOGG1 transgene mRNA were not detected at all in the above two organs from control mice, indicating that the transgene is highly expressed in the hematopoietic organs in TG mice. We then measured mitochondrial NADH dehydrogenase 1 (ND1) gene expression as an indirect measure of mitochondrial respiratory function. ND1 mRNA levels in the spleen (4) and lymphoma (4) of TG mice were 83% and 58% higher, respectively, than those in the spleen (4) of wild-type control mice (P < 0.01), indicative of increased mitochondrial respiration in the lymphoma and spleen of hOGG1 TG mice. We next measured the levels of intracellular H2O2 production in the lymphoma and spleen of hOGG1 transgenic (4) and the spleen from wild-type control (4) mice. The amount of H2O2 produced in the lymphoma and the spleen of hOGG1 transgenic mice was ~166% and ~66% higher, respectively, than that in the spleen from wild-type control mice (P < 0.001). The amount of H2O2 produced in the lymphoma was ~60% higher than that in the spleen from hOGG1 transgenic mice (P < 0.05). Finally, we examined mitochondrial DNA alterations in TG mice. Mitochondrial DNA samples were extracted from various organs and lymphoma tissues from hOGG1 TG and age-matched non-TG control animals and subjected to PCR analysis using specific primer sets franking the breakpoints of 7 major mitochondrial DNA deletions. Six deletions (3.7, 3.82, 3.86, 4.2, 4.9 and 5.2 kilobase in length) have been previously reported in the literatures. One novel deletion of 15.kilobase was identified in hOGG1 TG mouse in our laboratory. Among 7 major mitochondrial DNA deletion analyzed, Five (3.7, 3.86, 4.2, 5.2 and 15 kilobase in length) deletions were detected in higher frequency in various organs of hOGG1 TG but not in non-TG control mice, suggesting that those deletions might be resulted from overexpression of the transgene hOGG1. Notably, 3 deletions (del3729, del3868, and del15139) were present in significantly higher frequencies in spleen with myeloproliferative disorders or lymphoma from TG mice in comparison to the spleen of the age-matched wild type animals (P<0.01). While the precise mechanisms leading to the development of hematopoietic neoplasms remain elusive, we hypothesized that major mitochondrial gene deletions and increased mitochondrial respiration, as a result of overexpressed hOGG1 gene in the mitochondria, may contribute significantly to the increased intracellular ROS in hematopoietic progenitor cell populations, which, in turn, causes further genetic mutation and the development of lymphoma and myeloproliferative disorder seen in these TG mice. Disclosures No relevant conflicts of interest to declare.