Base excision repair modulation as a risk factor for human cancers

Altered DNA repair capacity can result in increased susceptibility to cancer. The base excision repair (BER) pathway effectively removes DNA damage caused by ionizing radiation and reactive oxidative species (ROS). In the current study, we analyzed the possible relation of polymorphisms in BER genes, including 8-oxoguanine DNA glycosylase (OGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and X-ray repair cross-complementing group 1 protein (XRCC1), with breast cancer risk in Chinese Han women. This case-control study examined 194 patients with breast cancer and 245 cancer-free hospitalized control subjects. Single nucleotide polymorphisms (SNPs) of OGG1 (Ser326Cys), XRCC1 (Arg399Gln), and APE1 (Asp148Glu and -141T/G) were genotyped and analyzed for their association with breast cancer risk using multivariate logistic regression models. We found that XRCC1 Arg399Gln was significantly associated with an increased risk of breast cancer. Similarly, the XRCC1 Gln allele was significantly associated with an elevated risk in postmenopausal women and women with a high BMI (≥ 24 kg/m 2 ). The OGG1 Cys allele provided a significant protective effect against developing cancer in women with a low BMI (< 24 kg/m 2 ). When analyzing the combined effects of these alleles on the risk of breast cancer, we found that individuals with ≥ 2 adverse genotypes (XRCC1 399Gln, APE1 148Asp, and OGG1 326Ser) were at a 2.18-fold increased risk of breast cancer (P = 0.027). In conclusion, our data indicate that Chinese women with the 399Gln allele of XRCC1 have an increased risk of breast cancer, and the combined effects of polymorphisms of BER genes may contribute to tumorigenesis.

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of DNA Base-excision Repair Genes (APE1, OGG1 and XRCC1) Associated with Breast Cancer Risk in a Chinese Population

Luo¹,

Li²,

Qu³

et al. 2014

“…XRCC1 gene is regarded an important proteins in the multistep BER pathway, and it is the first mammalian gene isolated that affects cellular sensitivity to ionizing radiation (Thompson et al, 1990). Mutations of XRCC1 may increase the risk of cancers by impairing the interaction of XRCC1 with other enzymatic proteins and consequently altering DNA repair activity (Basso et al, 2007;Tudek, 2007), and subsequently induce the carcinogenesis of head and neck and cancer of lung, esophagus, breast and many other malignancies (Yu et al, 2003;Han et al, 2004). As we known, HBV and HCV may promote chromosomal instability or insertional mutations, and thus to induce the carcinoma development risk.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of DNA Repair Gene XRCC1 Polymorphism in Prediction and Prognosis of Hepatocellular Carcinoma Risk

Li¹,

Lu²,

Ye³

et al. 2012

“…Amino acid substitutions in the BRCT domain and in the DNA polymerase β interacting domain in hamster is reported to disrupt the functionality of XRCC1 (Shen et al, 1998). The mutations of XRCC1 polymorphisms may increase the risk of cancers by impairing the interaction of XRCC1 with other enzymatic proteins and consequently altering DNA repair activity (Basso et al, 2007;Tudek, 2007), and resulted in carcinogenesis development. Our study found significant an odds ratio of codon 399 Gln allele for ovarian cancer, which strongly implicates that these polymorphisms may alter the normal protein function by encoding for a twisted protein (Tuimala et al, 2002), resulting in altered affinity to its interactive proteins suggesting an association with a deficiency in DNA repair capacity.…”

Section: Discussionmentioning

confidence: 99%

Predictive Value of XRCC1 and XRCC3 Gene Polymorphisms for Risk of Ovarian Cancer Death After Chemotherapy

Cheng

Xue²,

Li³

et al. 2012

Objective: To investigate any association between XRCC1 and XRCC3 polymorphisms and outcome of platinum-based chemotherapy in ovarian cancer patients. Methods: With a prospective study design was cases were consecutively collected from January 2005 to January 2007. All 310 included patients were followed-up until the end of January 2010. Genotyping of XRCC1 and XRCC3 polymorphisms was conducted by TaqMan Gene Expression assays. Results: A total of 191 patients died during follow-up. Our study showed a lower survival rate in XRCC1 399 Arg/Arg genotype than Gln/ Gln, with a significant increased risk of death (HR=1.69, 95%CI=1.07-2.78). Similarly, those carrying XRCC3 Thr/ Thr genotype had a increased risk as compare to the Met/Met genotype, with a HR (95% CI) of 1.90 (1.12-3.41). There was no significant association between XRCC1 Arg194Trp and XRCC1Arg280His gene polymorphisms and ovarian cancer death. Conclusion: Our study demonstrates that polymorphisms in DNA repair genes have roles in the susceptibility and survival of ovarian cancer patients.