Reduced levels of XPA, ERCC1 and XPF DNA repair proteins in testis tumor cell lines

Over 80% of patients with advanced metastatic testis tumors can be cured using cisplatin-based combination chemotherapy. This is unusual as metastatic cancer in adults is usually incurable. Cell lines derived from testis tumors retain sensitivity to cisplatin in vitro. We previously investigated 2 testis tumor cell lines with a low capacity to remove cisplatin-induced DNA damage and found that they had low levels of the DNA nucleotide excision repair proteins XPA, ERCC1 and XPF. To determine whether low levels of XPA, ERCC1 and XPF proteins are characteristic of testis tumor cell lines, we investigated 35 cell lines derived from cancers to determine whether groups of cell lines from diverse tissue origins differ from one another in constitutive levels of these NER proteins. Quantitative immunoblotting was used to compare groups of cell lines representing prostate, bladder, breast, lung, cervical, ovarian and testis cancers. Only the 6 testis tumor cell lines showed significantly lower mean levels of XPA (p = 0.001), XPF (p = 0.001) and ERCC1 (p = 0.004) proteins from the other groups. Our results encourage further investigation of the possibility that low levels of these nucleotide excision repair proteins could be related to the favorable response of testis tumors to cisplatin-based chemotherapy.     

Genomic copy number changes of DNA repair genes ERCC1 and ERCC2 in human gliomas

Abnormalities of the genomic region of chromosome 19q13.2–13.4 are a common occurrence in brain malignancies and contain a possible tumor suppressor gene involved in gliomas. Since abnormalities of DNA repair are associated with malignancy, we assessed DNA status of the nucleotide excision repair genes located in this area, viz. ERCC1 and ERCC2.Radiodensitometry was used to assess gene copy number in samples obtained from brain tumor specimens from 24 patients. Nine tumors were of lower grade histology (3 pilocytic astrocytomas, 2 gangliogliomas, 4 astrocytomas); 15 tumors were pathologiclly higher grade (4 anaplastic astrocytomas, 11 glioblastomas). Tumor samples were obtained prior to radiation or chemotherapy. Abnormalities of gene copy number of ERCC1 and ERCC2 were observed in 11/24 specimens (46%). Whereas increased and decreased copy numbers were observed for ERCC1, only decreases in copy number of ERCC2 were seen. Three tumors (all lower grade) showed concurrent allelic loss of ERCC1 and ERCC2. Abnormalities of copy number for these genes were not associated with response to subsequent therapy nor survival. However, allelic loss of ERCC2 was associated with younger age at diagnosis when compared to those specimens which did not show loss. There were no significant differences between lower grade and higher grade tumors with respect to these investigations.Abnormalities in copy number of ERCC1 and ERCC2 are common in glial tumors. Further study of this genomic region is necessary to define the importance of these observations in tumor pathophysiology and treatment.     

Decreased DNA repair activity in bone marrow due to low expression of DNA damage repair proteins

The bone marrow (BM) is one of the organs that is sensitive to acute exposure of ionizing radiation (IR); however, the mechanism of its high sensitivity to IR remains to be elucidated. BM is differentiated into dendritic cells (DC) with granulocyte macrophage-colony stimulating factor (GM-CSF). Using this in vitro model, we studied whether radiosensitivity is distinctly regulated in undifferentiated and differentiated BM. We discovered that levels of DNA damage repair (DDR) proteins are extremely low in BM, and they are markedly increased upon differentiation to DC. Efficiency of both homologous recombination (HR)- and non-homologous end joining (NHEJ)-mediated repair of DNA double strand breaks (DSBs) is much lower in BM compared with that of DC. Consistent with this, immunofluorescent γH2AX is highly detected in BM after IR. These results indicate that increased radiosensitivity of BM is at least due to low expression of the DNA repair machinery.     

Single nucleotide polymorphisms in the XPG gene: determination of role in DNA repair and breast cancer risk

In this study we determined the effect of single nucleotide polymorphisms in the XPG gene on DNA repair and breast cancer susceptibility. Ninety individuals, with previously studied DNA repair rate at 24 hr of 2 types of UV-specific cyclobutane pyrimidines dimers (CPDs) in skin were genotyped for XPG polymorphism at codon 1104 (exon 15 G>C; Asp > His). The repair rate of TT=C dimer was similar in both wild-type GG homozygotes and GC heterozygotes, whereas, for TT=T, dimer repair was non-significantly (Student's t-test, p = 0.34) lower in GC heterozygotes than wild-type GG homozygotes. Genotyping of 220 breast cancer cases and 308 controls for the same single nucleotide polymorphism in exon 15 of the XPG gene exhibited marginally significant increased frequency of the variant allele (chi(2) 3.84, p = 0.05; OR 1.33, 95% CI 1.0-1.8) in cases (C-allele 0.29) compared to controls (C-allele 0.24). Combined heterozygote and variant homozygote genotype frequency was also higher in cases than controls (chi(2) 4.79, p = 0.03; OR 1.50, 95%CI 1.04-2.16).     

Polymorphisms in the DNA nucleotide excision repair genes and lung cancer risk in Xuan Wei, China

The lung cancer mortality rate in Xuan Wei County is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Nucleotide excision repair (NER) plays a key role in reversing DNA damage from exposure to environmental carcinogens, such as PAHs, that form bulky DNA adducts. We studied single nucleotide polymorphisms (SNPs) and their corresponding haplotypes in 6 genes (ERCC1, ERCC2/XPD, ERCC4/XPF, ERCC5/XPG, RAD23B and XPC) involved in NER in a population-based case-control study of lung cancer in Xuan Wei. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled. Three linked SNPs in ERCC2 were associated with lung cancer with similar ORs; e.g., persons with the Gln allele at codon 751 had a 60% reduction of lung cancer (OR = 0.40, 95% CI 0.18-0.89). Moreover, one haplotype in ERCC2 was associated with a decreased risk of lung cancer (OR = 0.40, 95% CI 0.19-0.85) compared to the most common haplotype. In addition, subjects with one or 2 copies of the Val allele at codon 249 of RAD23B had a 2-fold increased risk of lung cancer (OR = 1.91, 95% CI 1.12-3.24). In summary, our results suggest that genetic variants in genes involved in the NER pathway may play a role in lung cancer susceptibility in Xuan Wei. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and in other populations with substantial environmental exposure to PAHs.     

Minimal deletion regions in lung squamous cell carcinoma: association with abnormality of the DNA double-strand break repair genes and their applications on gene identification and prognostic biomarkers

BACKGROUND: Lung squamous cell carcinoma (SCC) cells frequently exhibit markers of chromosome instability such as high fractional allelic loss (FAL). We postulated that alterations in the p53 damage responsive gene and in the double-strand break (DSB) repair genes, BRCA1 and XRCC5, are involved in patients with high FAL. In addition, chromosomal deletion analysis enables the delineation of the likely locations of tumor suppressor genes (TSG) and could provide molecular markers for disease classification. PATIENTS AND METHODS: To define the minimal deletion regions (MDRs), we used 92 microsatellites spanning 29 regions identified in our previous genome-wide chromosomal deletion study in 36 lung SCC patients to verify the maximal contiguous deletion loci. RESULTS: Eight MDRs at 2q35, 3p14.1-3p14.3, 3p22.2-p23, 3p25.3-3p26.3, 5q35.1-q35.2, 9p23-p24.1, 13q14.11-q14.2, and 17p13.1-p13.2 were found in lung SCC. The candidate genes GAS7 and OVCA2 in the MDR17pA (17p13.1-p13.2) were further examined for mRNA expression. Low expression of the GAS7 gene in 57% of patients analyzed suggested its importance in lung SCC tumorigenesis. In addition, we found a panel of five microsatellites (D3S1766, D4S2397, D4S2361, D13S175, and D17S974), which can be used as prognostic biomarkers in lung SCC. Furthermore, alteration in more than two genes in DSB repair-related pathways was more apparent in high FAL patients. CONCLUSIONS: Our results provide biomarkers that may be used for monitoring tumor progression and for positional cloning of new TSGs. Importantly, our data show direct evidence that alterations in DSB repair-related pathways are involved in the genomic instability verified by intensive microsatellites of lung SCC.     

Variation in PAH‐related DNA adduct levels among non‐smokers: The role of multiple genetic polymorphisms and nucleotide excision repair phenotype

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never‐smokers. We tried to find a model to explain the relationship between variation in PAH‐related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never‐smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by 32 P‐postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10⁸ nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non‐risk‐allele genotype, and was higher in the MPO homozygote risk‐allele genotype. The sum of risk alleles in these genes significantly correlated with the log‐adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non‐smokers in this population had PAH‐related DNA adduct levels three to four times higher than smokers and occupationally‐exposed groups in previous studies, with large inter‐individual variation which could best be explained by a combination of Phase I genes and NER capacity.     

ERCC2/XPD基因缺失对苯并[a]芘所致DNA损伤修复的影响

目的： 探讨核苷酸切除修复交叉互补基因2 (excision repair cross complementation group 2/Xeroderma pigmentosum D,ERCC2/XPD)在苯并[a]芘所诱导的细胞DNA损伤与修复过程中的作用。方法：应用中国仓鼠卵巢细胞系CHO野生型AA8和ERCC2表达缺失型UV5作为细胞对照模型,MTT法比较两种细胞经苯并[a]芘处理后细胞抑制率的差别;彗星试验和Rad51免疫荧光试验检测不同浓度苯并[a]芘处理及修复24 h后细胞DNA损伤修复的情况。结果：与野生型AA8细胞相比,UV5细胞对苯并[a]芘所致损伤更加敏感,细胞存活率降低 (P<0.05)。彗星试验和Rad51免疫荧光试验结果显示,UV5细胞由于缺失ERCC2/XPD基因,修复苯并[a]芘所致DNA损伤能力降低 (P<0.05)。 结论：ERCC2/XPD蛋白在核苷酸切除修复中发挥解旋作用,对苯并[a]芘所致DNA损伤修复至关重要。     

Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas

Overexpression of ERCC1 mRNA is associated with drug resistance to cisplatin in human gliomas, but the role of the ERCC1 promoter in drug resistance has not been demonstrated. We have used sodium bisulfite sequencing to compare ERCC1 promoter methylation patterns in cisplatin‐sensitive and cisplatin‐resistant glioma cells. The levels of ERCC1 DNA methylation, mRNA and protein in 32 human glioma samples were examined by methylation specific PCR, real‐time RT‐PCR and immunohistochemistry, respectively. Meanwhile, cisplatin sensitivities to these human glioma samples were tested by histoculture drug response assay. Hypermethylation was observed in the upstream 5Kb region of the ERCC1 promoter of cisplatin‐sensitive glioma cell lines. ERCC1 DNA methylation levels were highly variable in 32 human glioma samples ranging from 0.1 to 0.87, which have shown significant difference between cisplatin‐sensitive samples and cisplatin‐resistant samples (p < 0.05). The relative expression levels of ERCC1 mRNA in 32 glioma samples were also variable from 0.01 to 5.71. No detectable or low expression of ERCC1 protein was shown in 7 glioma samples. ERCC1 promoter methylation was inversely correlated to mRNA expression (r = ?0.903 p = 0.001) as well as protein expression (r = ?0.884 p = 0.001). Moreover, ERCC1 mRNA expression was significantly associated with protein levels (r = 0.840 p = 0.001). In summary, the aberrant CpG island methylation in ERCC1 promoter region exists in human glioma cell lines as well as clinical glioma samples. ERCC1 DNA methylation could regulate the expression of downstream mRNA and protein, and was associated with cisplatin chemosensitivity.     

5 Aza CdR通过DNMT1调控卵巢癌细胞ERCC1基因甲基化及其表达

目的:研究5-氮杂-2'-脱氧胞苷(5-Aza-CdR)在卵巢癌细胞系SKOV3中对核苷酸切除交叉修复互补基因1(exeision repair cross complementation group 1,ERCC1)表达的影响及可能的机制.方法:设计特异性针对DNA甲基转移酶1(DNAmethyhransferase 1,DNMT1)基因的shRNA转染人人卵巢癌细胞系SKOV3细胞中,Western blotting检测SKOV3细胞DNMT1以及ERCC1的表达变化;利用不同浓度5-Aza-CdR于不同时间点处理卵巢癌SKOV3细胞,Western blotting检测DNMTI和ERCC1蛋白在处理前后的变化,利用亚硫酸氢钠法检测ERCC1基因启动子区域甲基化水平.结果:0.5、1.0、2.0、4.0μmol/L的5-Aza-CdR作用于SKOV3细胞后,DNMT1表达水平呈浓度依赖性降低,而ERCC1表达水平呈浓度依赖性升高;使用终浓度为1.0 μmol/L的5-Aza-CdR处理SKOV3细胞12、24、36 h后,DNMT1表达水平呈时间依赖性降低,而ERCC1表达水平呈时间依赖性升高,亚硫酸氢钠法检测示药物处理前ERCC1启动子区域处于高甲基化水平,在用1.0μmol/L的5-Aza-CdR处理后,其启动子发生了去甲基化.结论:5-Aza-CdR通过DNMT1调控卵巢癌SKOV3细胞中ERCC1基因的甲基化及其表达水平.     

Genetic variants in DNA repair pathways are not associated with disease progression among multiple myeloma patients

DNA damage induced by high dose melphalan and autologous transplantation is repaired by the nucleotide excision repair (NER) and base excision repair (BER) pathways. We evaluated the association between single nucleotide polymorphisms (SNPs) (n = 311) in the NER and BER pathways and disease progression in 695 multiple myeloma patients who underwent autologous transplantation. None of the SNPs were associated with disease progression. Pathway based analyses showed that the NER pathway had a borderline association with disease progression (p = 0.09). These findings suggest that common variation in the NER and BER pathways do not substantially influence disease progression in multiple myeloma patients.     

DNA mismatch repair gene polymorphisms affect survival in pancreatic cancer

Purpose.

DNA mismatch repair (MMR) maintains genomic stability and mediates cellular response to DNA damage. We aim to demonstrate whether MMR genetic variants affect overall survival (OS) in pancreatic cancer.

Materials and Methods.

Using the Sequenom method in genomic DNA, we retrospectively genotyped 102 single-nucleotide polymorphisms (SNPs) of 13 MMR genes from 706 patients with pancreatic adenocarcinoma seen at The University of Texas MD Anderson Cancer Center. Association between genotype and OS was evaluated using multivariable Cox proportional hazard regression models.

Results.

At a false discovery rate of 1% (p ≤ .0015), 15 SNPs of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, TP73, and TREX1 in patients with localized disease (n = 333) and 6 SNPs of MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease (n = 373) were significantly associated with OS. In multivariable Cox proportional hazard regression models, SNPs of EXO1, MSH2, MSH3, PMS2L3, and TP73 in patients with localized disease, MSH2, MSH3, MSH6, and TP73 in patients with locally advanced or metastatic disease, and EXO1, MGMT, MSH2, MSH3, MSH6, PMS2L3, and TP73 in all patients remained significant predictors for OS (p ≤ .0015) after adjusting for all clinical predictors and all SNPs with p ≤ .0015 in single-locus analysis. Sixteen haplotypes of EXO1, MLH1, MSH2, MSH3, MSH6, PMS2, PMS2L3, RECQL, TP73, and TREX1 significantly correlated with OS in all patients (p ≤ .001).

Conclusion.

MMR gene variants may have potential value as prognostic markers for OS in pancreatic cancer patients.     

XRCC1单核苷酸多态性与结直肠癌风险的关系

背景与目的:X线交叉互补基因1(X-ray repair cross complementing group 1,XRCC1)编码蛋白在DNA单链断裂修复和DNA碱基修复过程中起重要作用.该基因外显子多态性的存在可影响编码蛋白的功能活性,最终使机体对癌症的易感性发生变化.本研究旨在探讨该基因外显子最常见的3处单核苷酸多态(single nucleotide polymorphism,SNP)--C26304T、G27466A和G28152A与结直肠癌风险的关系.方法:以聚合酶链反应(polymerase chain reaction,PCR)和限制性片段长度多态性(restrictive fragment length polymorphism,RFLP)分析方法,检测207例结直肠癌病例和621例成组匹配的正常对照XRCC1 C26304T、G27466A和G28152A基因型,并比较不同基因型与结直肠癌风险的关系.采用EH Linkage Software 1.2统计分析软件对研究对象的单体型分布进行预测.结果:年龄、性别、身体质量指数(body mass index,BMI)等个体特征,以及吸烟、饮酒等常见环境暴露因素的分布和/或构成比在结直肠癌病例组和对照组间差异均无显著性(P＞0.05).对XRCC1各多态基因型检测分型发现,结直肠癌病例组携带26304T、27466A和28152A变异等位基因的频率分别为29.95%、11.22%和28.22%,对照组分别为32.87%、12.34%和27.27%,各多态等位基因在两组间分布均没有显著性差异(P＞0.05).各多态基因型分布经x2拟合优度检验均符合Hardy-Weinberg平衡定律,且在两组间都没有显著性差异(P＞0.05).没有观察到各多态基因型与结直肠癌发病风险存在显著相关关系(P＞0.05).单体型分析发现,各变异等位基因在病例组和对照组内均存在遗传连锁不平衡现象,CGG、CGA、CAG和TGG是最常见的4类单体型,其在两组的分布频率总和分别为95.54%和96.64%,然而在两组间同样不存在显著性差异(P＞0.05).结论:我国浙江省嘉善县人群中,XRCC1 C26304T、G27466A和G28152A基因多态性与结直肠癌发病风险不存在相关性,然而各变异等位基因存在遗传连锁不平衡现象,CGG、CGA、CAG和TGG是最常见的4类单体型.     

Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to glioma

Background: The XRCC1 gene encodes the XRCC1 protein, which complexes with three other DNA repair enzymes involved in the base-excision repair (BER) pathways. Different XRCC1 polymorphisms may increase the risk of cancers by impairing interaction with other enzymatic proteins and consequently altering DNA repair activity, and result in carcinogenesis. Our study aimed to investigate any association between three polymorphisms of the XRCC1 gene at codon 194, 280 and 399 and potential glioma risk. Methods: We collected 127 patients with primary glioma and 249 controls who requested general health examinations from Union Hospital of Tongji Medical College hospital from March 2007 to September 2010. A total of 5 ml venous blood was drawn from each subject. The polymorphisms of XRCC1 gene at codons 194, 280 and 399 were analyzed based on duplex polymerase-chain-reactions with the confronting-two-pair primer (PCR-CTPP) method. Results: The homozygous Trp/Trp and heterozygotes Arg/Trp variants of codon 194 had a 2.12 fold and 1.46 fold increased risk of glioma compared to the homozygous Arg/Arg wide genotypes. The same effect was found in codon 399, the codon 399 Gln/Gln and Arg/Gln genotypes being associated with a 2.24 fold and 1.67 fold increased risk in glioma. When comparing the codon 194 Arg/Arg and 399 Arg/Arg genotypes, the combination of codon 194 Trp allele and 399 Gln allele had a heavy increase in glioma risk (OR=2.87, 95%CI=1.56-6.73). Conclusion: The present study provided evidence of a potential role for XRCC1 codon 194 and 399 polymorphisms in genetic predisposition to glioma among the Chinese population. This analysis of correlation of DNA repair genes and glioma may provide a deeper insight into the genetic and environment factors for cancer risk.     

乙肝病毒对DNA修复基因和肝癌发生的作用

目的　以HBV转基因动物模型研究乙型肝炎病毒 (HBV) ,黄曲霉毒素 (AFB1) ,DNA修复基因和肝细胞肝癌 (HCC)发生的关系。方法　对HBVx基因转基因小鼠以相同的方式和剂量给予黄曲霉毒素 (AFB1)攻击 ,比较肝癌的发生率 ;同时用逆转录———热标记扩增 (RT -HOT -PCR)的方法 ,检查HBVx基因转基因小鼠HBVx整合阳性和阴性以及AFB1攻击后 ,癌组织与癌旁组织的DNA修复基因Brca2和Nthl1的RNA表达水平。结果　 (1)黄曲霉毒素诱导 ,5 2周肝癌发生率HBVx整合阳性小鼠 2 9只 ,14只发生肝癌 (48.3% ) ;HBVx整合阴性小鼠 15只 ,3只发生肝癌 (2 0 .0 % )。两者有显著的差异 (P <0 .0 1)。(2 )HBVx整合阳性小鼠的肝组织DNA修复基因Brca2和Nthl1的RNA表达水平都低于HBVx整合阴性小鼠。经AFB1攻击形成的肝癌和癌旁组织 ,其DNA修复基因Brca2和Nthl1的RNA表达水平也低于HBVx整合阴性小鼠。结论　结果表明HBVx在宿主细胞的整合 ,影响了宿主DNA修复能力 ,从而导致宿主对致癌物质的敏感性增加 ,最终引起肝癌发生率的增加。     

The role of DNA repair capacity in susceptibility to lung cancer: A review

Human cancer risk assessment has relied largely on animal experiments and use of short-term biological tests based on chemical-DNA interaction. The recent introduction of biomarkers to molecular epidemiologic studies has provided another means of assessing risk for tobacco-related cancer. Several biomarkers for genetic susceptibility to lung cancer have been developed and validated in pilot studies that have demonstrated their association with increased risk of lung cancer. For instance, metabolic enzymes responsible for bioactivation and detoxification of environmental chemicals, carcinogen-induced DNA adducts and chromosomal aberrations, and host DNA repair capacity have been measured in human peripheral lymphocytes. These markers allow estimation of interindividual variation in response to carcinogen exposure and thus assessment of cancer risk. Therefore, epidemiological studies of exposure and of molecular etiology of human carcinogenesis provide a new avenue of cancer risk assessment.     

Cytogenetic damage and genetic variants in the individuals susceptible to arsenic-induced cancer through drinking water

In West Bengal, India, more than 300,000 arsenic-exposed people are showing symptoms of arsenic toxicity, which include cancers of skin and different internal organs. Since only 15-20% of the exposed population manifest arsenic-induced skin lesions, it is thought that genetic variation might play an important role in arsenic toxicity and carcinogenicity. A total of 422 unrelated arsenic-exposed subjects (244 skin-symptomatic and 178 asymptomatic) were recruited for this study. Cytogenetic damage, as measured by chromosomal aberrations in lymphocytes and micronuclei formation in oral mucosa cells, urothelial cells and binucleated lymphocytes, was studied in unexposed, skin-symptomatic and asymptomatic individuals with similar socioeconomic status. Identification of null mutations in GSTT1 and GSTM1 genes were carried out by PCR amplification. GSTP1 SNPs, implicated in susceptibility to various cancers, were assessed by PCR-RFLP method. Symptomatic individuals had higher level of cytogenetic damage compared to asymptomatic individuals and asymptomatic individuals had significantly higher genotoxicity than unexposed individuals. No difference in allelic variants in GSTT1 and GSTP1 was observed between these 2 groups. Incidence of GSTM1 null gene frequencies was significantly higher in the asymptomatic group. Individuals with GSTM1-positive (at least one allele) had significantly higher risk of arsenic-induced skin lesions (odds ratio, 1.73; 95% confidence interval, 1.24-2.22). These results show a protective role of GSTM1 null in arsenic toxicity. This study also indicates that asymptomatic individuals are sub clinically affected and are also significantly susceptible to arsenic-induced genotoxicity.     

DNA Repair Gene Polymorphisms and Susceptibility to Urothelial Carcinoma in a Southeastern European Population

Single nucleotide polymorphisms (SNPs) in DNA repair genes may predispose to urothelial carcinoma of the bladder (UCB). This study focused on three specific SNPs in a population with high exposure to environmental carcinogens including tobacco and alcohol. A case-control study design was used to assess for presence of XPC PAT +/−, XRCC3 Thr241Met, and ERCC2 Lys751Gln DNA repair gene SNPs in peripheral blood from patients with UCB and healthy individuals. One hundred patients and equal number of healthy subjects were enrolled. The XPC PAT +/+ genotype was associated with a 2-fold increased risk of UCB (OR = 2.16; 95%CI: 1.14–4; p = 0.01). The −/+ and +/+ XPC PAT genotypes were more frequently present in patients with multiple versus single tumors (p = 0.01). No association was detected between ERCC2 Lys751Gln genotypes/alleles, and risk for developing UCB. Presence of the XRCC3 TT genotype (OR = 0.14; 95%CI:0.07–0.25; p < 0.01) and of the T allele overall (OR = 0.26; 95%CI:0.16–0.41; p < 0.01) conferred a protective effect against developing UCB. The XPC PAT −/+ and XRCC3 Thr241Met SNPs are associated with predisposition to UCB. The XPC PAT −/+ SNP is also an indicator of bladder tumor multiplicity, which might require a more individualized surveillance and treatment.     

碱基切除修复基因APE和XRCC1表达与大肠癌发生相关性的探讨

目的:通过检测大肠癌、癌旁黏膜与正常黏膜中APE和XRCC1蛋白的表达,探讨大肠癌的发生机制.方法:选取大肠癌手术切除标本185例,其中32例标本取癌旁黏膜组织;正常黏膜组织36例.通过免疫组化方法检测APE和XRCC1蛋白在癌、癌旁黏膜和正常黏膜的表达.结果:大肠癌、癌旁黏膜组APE阳性表达率分别为78.9％(146/185)和81.2％(26/32),两者均明显高于正常黏膜组的61.1％(22/36),x2值分别为5.23和4.86,P值分别为0.024和0.03,但前两者APE表达差异无统计学意义.大肠癌中APE蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浆膜浸润及淋巴结转移无明显相关关系.大肠癌与癌旁黏膜组XRCC1阳性表达率分别为94.6％(175/185)和87.5％(27/32),两者均明显高于正常黏膜组的27.7％(10/36),x2值分别为4.43和29.69,P值分别为0.036和0.002,但前两者间差异无统计学意义.大肠癌中XRCC1蛋白表达与患者性别、年龄、肿瘤部位、分化程度、浆膜浸润及淋巴结转移无明显相关关系.大肠癌XRCC1阳性组的APE阳性率为95.8％(136/142),显著高于大肠癌XRCC1阴性组的86.0％(37/43),XRCC1与APE两者表达呈明显正相关关系,r=0.354,P=0.02.大肠癌和癌旁黏膜组的APE和XRCC1蛋白同时表达的阳性率分别为75.8％(140/185)和65.6％(21/32),两组均明显高于正常黏膜组的16.7％(6/36),x2值分别为46.8和16.17,P值分别为0.001和0.001 5,但癌组与癌旁组间差异无统计学意义.结论:大肠癌和癌旁黏膜中存在APE和XRCC1表达上调.大肠癌发生可能与DNA复制时位点损伤及烷化剂等有毒物质损伤关系密切,同时检测大肠黏膜不同种类DNA修复基因的表达有助于大肠癌的早期诊断.