Research IndicatorsGraph generated 15 March 2017 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex
Specific Cancers (6)
Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
GEO Profiles, NCBI
Search the gene expression profiles from curated DataSets in the Gene Expression Omnibus (GEO) repository.
Latest Publications: XRCC2 (cancer-related)
Singh SA, Ghosh SKPolymorphisms of XRCC1 and XRCC2 DNA Repair genes and Interaction with Environmental Factors Influence the Risk of Nasopharyngeal Carcinoma in Northeast India.
Asian Pac J Cancer Prev. 2016; 17(6):2811-9 [PubMed
] Related Publications
Multiple genetic and environmental factors have been reported to play key role in the development of nasopharyngeal carcinoma (NPC). Here, we investigated interactions of XRCC1 Arg399Gln and XRCC2 Arg188His polymorphisms and environmental factors in modulating susceptibility to NPC in Northeast India. One-hundred NPC patients, 90 first-degree relatives of patients and 120 controls were enrolled in the study. XRCC1 Arg399Gln and XRCC2 Arg188His polymorphisms were determined using PCR-RFLP, and the results were confirmed by DNA sequencing. Logistic regression (LR) and multifactor dimensionality reduction (MDR) approaches were applied for statistical analysis. The XRCC1 Gln/Gln genotype showed increased risk (OR=2.76; <0.024) of NPC. However, individuals with both XRCC1 and XRCC2 polymorphic variants had 3.2 fold elevated risk (<0.041). An enhanced risk of NPC was also observed in smoked meat (OR=4.07; P=0.004) and fermented fish consumers (OR=4.34, P=0.001), and tobacco-betel quid chewers (OR=7.00; P=0.0001) carrying XRCC1 polymorphic variants. However, smokers carrying defective XRCC1 gene showed the highest risk (OR = 7.47; <0.0001). On MDR analysis, the best model for NPC risk was the five-factor model combination of XRCC1 variant genotype, fermented fish, smoked meat, smoking and chewing (CVC=10/10; TBA=0.636; <0.0001); whereas in interaction entropy graphs, smoked meat and tobacco chewing showed synergistic interactions with XRCC1. These findings suggest that interaction of genetic and environmental factors might increase susceptibility to NPC in Northeast Indian populations.
Kleibl Z, Kristensen VNWomen at high risk of breast cancer: Molecular characteristics, clinical presentation and management.
Breast. 2016; 28:136-44 [PubMed
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The presence of breast cancer in any first-degree female relative in general nearly doubles the risk for a proband and the risk gradually increases with the number of affected relatives. Current advances in molecular oncology and oncogenetics may enable the identification of high-risk individuals with breast-cancer predisposition. The best-known forms of hereditary breast cancer (HBC) are caused by mutations in the high-penetrance genes BRCA1 and BRCA2. Other genes, including PTEN, TP53, STK11/LKB1, CDH1, PALB2, CHEK2, ATM, MRE11, RAD50, NBS1, BRIP1, FANCA, FANCC, FANCM, RAD51, RAD51B, RAD51C, RAD51D, and XRCC2 have been described as high- or moderate-penetrance breast cancer-susceptibility genes. The majority of breast cancer-susceptibility genes code for tumor suppressor proteins that are involved in critical processes of DNA repair pathways. This is of particular importance for those women who, due to their increased risk of breast cancer, may be subjected to more frequent screening but due to their repair deficiency might be at the risk of developing radiation-induced malignancies. It has been proven that cancers arising from the most frequent BRCA1 gene mutation carriers differ significantly from the sporadic disease of age-matched controls in their histopathological appearances and molecular characteristics. The increased depth of mutation detection brought by next-generation sequencing and a better understanding of the mechanisms through which these mutations cause the disease will bring novel insights in terms of oncological prevention, diagnostics, and therapeutic options for HBC patients.
Yan L, Li Q, Li X, et al.Association Studies Between XRCC1, XRCC2, XRCC3 Polymorphisms and Differentiated Thyroid Carcinoma.
Cell Physiol Biochem. 2016; 38(3):1075-84 [PubMed
] Related Publications
BACKGROUND/AIMS: DNA HRR pathway and BER pathway play vital roles in differentiated thyroid cancer (DTC) development, thus we supposed that polymorphisms of XRCC1, XRCC2, XRCC3 DNA repair genes are associated with thyroid cancer risk and progression.
METHODS: We searched the NCBI database for relevant literatures to determine eight SNPs to be included in our study (XRCC1: rs25487, rs25489, rs1799782; XRCC2: rs3218536; XRCC3: rs1799794, rs56377012, rs1799796, rs861539).
RESULTS: SNP of rs25487 was linked with a 53% decrease in DTC risk (OR: 0.47; 95%CI: 0.268-0.82; P = 0.01). For SNP of rs1799782, the homozygous TT genotype indicated a statistically significant 2-fold increased risk of DTC (OR: 2.09; 95%CI: 1.27-3.43; P < 0.001) after multivariate adjustment. For SNP of rs861539, the homozygous TT genotype suggested statistically significant 3-fold increased risk of DTC (OR: 3.02; 95%CI: 1.68-5.42; P < 0.001). No significant association between the other five SNPs and DTC risk. Besides that, female was linked with 47% increase in DTC risk (OR: 1.47; 95%CI: 1.062-2.04; P = 0.02) after multivariate adjustment. Similar results for most of the SNPs were obtained from subgroup analysis by different histological types of DTC. Haplotype analysis revealed that AGC and GGT haplotypes of XRCC1 polymorphisms were associated with DTC. Moreover, results from gene-gene interaction showed that XRCC1-rs25487, XRCC1- rs1799782 and XRCC3- rs861539 variants jointly contributed to a specifically increased risk of DTC, with the combination variant of rs1799782-CT heterozygote and rs861539-TT homozygote exhibiting a higher 3.66-fold risk of DTC (OR: 3.66; 95% CI: 1.476-9.091, P = 0.005).
CONCLUSION: Polymorphisms of XRCC1 (rs25487, rs1799782) and XRCC3 (rs861539), may play a critical role in DTC development and progression. Furthermore, XRCC1 variant can interact with XRCC3 variant to significantly increase DTC susceptibility. Identifying these genetic risk markers could provide evidence for exploring the insight pathogenesis and develop novel therapeutic strategies for DTC.
Michalska MM, Samulak D, Romanowicz H, et al.Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and ovarian cancer in Polish women.
Exp Mol Pathol. 2016; 100(2):243-7 [PubMed
] Related Publications
The variability, perceived in DNA repair genes, may be of clinical importance for evaluation of the risk of occurrence of a given type of cancer, its prophylactics and therapy. The aim of the present work was to evaluate associations between the risk of ovarian cancer and polymorphisms in the genes, encoding for two key proteins of homologous recombination: XRCC2 Arg188His (c. 563 G>A; rs3218536) and XRCC3 Thr241Met (c. 722 C>T; rs861539). The study consisted of 700 patients with ovarian cancer and 700 healthy subjects. Analysis of the gene polymorphisms was performed using PCR-RFLP (restriction length fragment polymorphism). We found a statistically significant increase of the 188His allele frequency (OR=4.01; 95% CI=3.40-4.72; p<.0001) of XRCC2 in ovarian cancer compared to healthy controls. There were no differences in the genotype and allele distributions and odds ratios of the XRCC3 Thr241Met polymorphism between patient and control groups. Association of these genetic polymorphisms with histological grading showed increased XRCC2 188Arg/His (OR=33.0; 95% CI=14.51-75.05; p<.0001) and 188His/His genotypes (OR=9.37; 95% CI=4.79-18.32; p<.0001) and XRCC3 241Thr/Met (OR=24.28; 95% CI=12.38-47.61; p<.0001) and 241Met/Met genotype frequencies (OR=17.00; 95% CI=8.42-34.28; p<.0001) in grading 1 (G1) as well as 188His (OR=2.78; 95% CI=2.11-3.69; p<.0001) and 241Met allele overrepresentation (OR=2.59; 95% CI=2.08-3.22; p<.0001) in G1 ovarian patients. Finally, with clinical FIGO staging under evaluation, an increase in XRCC2 188His/His homozygote and 188Arg/His heterozygote frequencies in staging I (SI) and XRCC3 Thr/Met heterozygote frequencies in SI was observed. The obtained results indicate that XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be positively associated with the incidence of ovarian carcinoma in the population of Polish women.
Gong H, Li H, Zou J, et al.The relationship between five non-synonymous polymorphisms within three XRCC genes and gastric cancer risk in a Han Chinese population.
Tumour Biol. 2016; 37(5):5905-10 [PubMed
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We aimed to assess the association of five non-synonymous polymorphisms within three X-ray repair cross-complementing group (XRCC) genes with gastric cancer risk in Han Chinese. Genotyping was determined in 693 gastric cancer patients and 681 healthy controls. Statistical analyses were completed with SPSS (version 20.0) and Haplo.stats (version 1.6.11). The genotypes of XRCC1 gene rs25487 polymorphism (P = 0.003) differed significantly between patients and controls, even after the Bonferroni correction (P < 0.05/5), and this polymorphism was significantly associated with gastric cancer after adjusting for age, sex, body mass index, smoking, drinking, especially under a dominant model (odds ratio or OR; 95 % confidence interval or CI; P 1.59; 1.20-2.00; 0.001). In multiple-marker analysis, the most common allele combination was C-G-G-G-C (alleles in order of rs1799782, rs25489, rs25487, rs3218536, rs861539), which was overrepresented in controls relative to patients (adjusted simulated P = 0.0001). Contrastingly, the frequency of allele combination C-G-A-G-C was significantly higher in patients than in controls (adjusted simulated P = 0.0009), and this combination was associated with a strikingly increased risk of gastric cancer (OR; 95 % CI; P 2.39; 1.32-4.31; 0.0040) after the Bonferroni correction (P < 0.05/11) and adjusting for confounders. Our findings demonstrated that XRCC1 gene rs25487 polymorphism might play a leading role in pronounced susceptibility to gastric cancer in Han Chinese.
Zhai M, Wang Y, Jiang MFArg188His polymorphism in the XRCC2 gene and the risk of ovarian cancer: a meta-analysis.
Genet Mol Res. 2015; 14(3):10808-15 [PubMed
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Numerous studies have evaluated the association between the Arg188His polymorphism of the X-ray repair cross-complementing group 2 (XRCC2) gene and ovarian cancer risk. However, the specific association is still controversial. This meta-analysis was therefore designed to clarify these controversies. Relevant case-control studies were enrolled in the meta-analysis. Quality evaluation of the included studies was conducted by two physicians. Statistical analyses were carried out using the Stata 12.0 software for meta-analysis. Analyses of sensitivity and publication bias were also conducted. Overall, a significant association was found between the Arg188His polymorphism and ovarian cancer risk when all studies were pooled into the meta-analysis (Arg/Arg vs His/His: OR = 1.85, 95%CI = 1.15-3.00; Arg/Arg vs Arg/His: OR = 1.17, 95%CI = 1.03-1.32; dominant model: OR = 0.84, 95%CI = 0.74-0.95; recessive model: OR = 1.69, 95%CI = 1.05-2.70). This meta-analysis suggested that the XRCC2 Arg188His polymorphism was associated with the risk of ovarian cancer. Further large and well-designed studies are needed to confirm these conclusions.
The Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) recently performed a genome-wide association study (GWAS) on esophageal adenocarcinoma (EAC) and Barrett's esophagus. They identified genome-wide significant association for variants at three genes, namely CRTC1, FOXP1, and BARX1. Furthermore, they replicated an association at the FOXF1 gene that has been previously found in a GWAS on Barrett's esophagus. We aimed at further replicating the association at these and other loci that showed suggestive association with P < 10(-4) in the BEACON sample. In total, we tested 88 SNPs in an independent sample consisting of 1065 EAC cases and 1019 controls of German descent. We could replicate the association at FOXP1, BARX1, and FOXF1 with nominal significance and thereby confirm that genetic variants at these genes confer EAC risk. In addition, we found association of variants near the genes XRCC2 and GATA6 that were strongly (P < 10(-5) ) although not genome-wide significantly associated with the BEACON GWAS. Therefore, both variants and corresponding genes represent promising candidates for future EAC association studies on independent samples.
BACKGROUND: Platinum compounds are the mainstay of chemotherapy for lung cancer. Unfortunately treatment failure remains a critical issue since about 60% of all non-small cell lung cancer (NSCLC) patients display intrinsic platinum resistance.
METHODS: We analyzed global gene expression profiles of NSCLC clones surviving a pulse treatment with cisplatin and mapped deregulated signaling networks in silico by Ingenuity Pathway Analysis (IPA). Further validation was done using siRNA.
RESULTS: The pooled cisplatin-surviving NSCLC clones from each of the biological replicates demonstrated heterogeneous gene expression patterns both in terms of the number and the identity of the altered genes. Genes involved in Wnt signaling pathway (Dickkopf-1, DKK1), DNA repair machinery (XRCC2) and cell-cell/cell-matrix interaction (FMN1, LGALS9) were among the top deregulated genes by microarray in these replicates and were validated by q-RT-PCR. We focused on DKK1 which previously was reported to be overexpressed in NSCLC patients. IPA network analysis revealed coordinate up-regulation of several DKK1 transcriptional regulators (TCF4, EZH2, DNAJB6 and HDAC2) in cisplatin-surviving clones from that biological replicate. Knockdown of DKK1 by siRNA sensitized for cisplatin in two different NSCLC cell lines and in ovarian A2780 cells, but not in the A2780 cis subline made resistant to cisplatin by chronic exposure, suggesting a role of DKK1 in intrinsic but not acquired platinum refractoriness.
CONCLUSIONS: We identified DKK1 as a possible marker of a cisplatin-refractory phenotype and as a potential novel therapeutic target to improve platinum response of NSCLC cells.
Pelttari LM, Kinnunen L, Kiiski JI, et al.Screening of HELQ in breast and ovarian cancer families.
Fam Cancer. 2016; 15(1):19-23 [PubMed
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Several high and moderate risk alleles have been identified for breast and ovarian cancer predisposition and most of them encode proteins that function in DNA repair. A prospective candidate for breast and ovarian cancer susceptibility is the HELQ helicase that has a role in the resolution of DNA interstrand cross-links. HELQ interacts with the RAD51 paralog complex BCDX2. Two components of the complex, RAD51C and RAD51D, increase the risk of ovarian cancer especially, and the other two, RAD51B and XRCC2 have been associated with breast cancer risk. To investigate the role of HELQ in cancer predisposition, we screened the gene for germline variation in 185 Finnish breast or ovarian cancer families and performed haplotype analyses for 1517 breast cancer cases, 308 ovarian cancer cases, and 1234 population controls using five common polymorphisms at the HELQ gene locus. No truncating mutations were identified among the families. One putatively pathogenic missense mutation c.1309A>G was identified but no additional carriers were observed in the subsequent genotyping of 332 familial breast or ovarian cancer patients. Furthermore, the haplotype distribution did not differ between breast or ovarian cancer cases and population controls. Our results indicate that HELQ is not a major breast and ovarian cancer susceptibility gene in the Finnish population. However, we cannot rule out rare risk-variants in the Finnish or other populations and larger datasets are needed to further assess the role of HELQ especially in ovarian cancer predisposition.
Genetic polymorphisms in DNA repair genes may induce individual variations in DNA repair capacity, which may in turn contribute to the risk of cancer developing. Homologous recombination repair (HRR) plays a critical role in maintaining chromosomal integrity and protecting against carcinogenic factors. The aim of the present study was to evaluate the relationship between prostate cancer risk and the presence of single nucleotide polymorphisms (SNPs) in the genes involved in HRR, that is, RAD51 (rs1801320 and rs1801321), RAD51B (rs10483813 and rs3784099), XRCC2 (rs3218536), and XRCC3 (rs861539). Polymorphisms were analyzed by PCR-RFLP and Real-Time PCR in 101 patients with prostate adenocarcinoma and 216 age- and sex-matched controls. A significant relationship was detected between the RAD51 gene rs1801320 polymorphism and increased prostate cancer risk. Our results indicate that the RAD51 gene rs1801320 polymorphism may contribute to prostate cancer susceptibility in Poland.
XRCC2 has been shown to increase the radioresistance of some cancers. Here, XRCC2 expression was investigated as a predictor of preoperative radiotherapy (PRT) treatment response in locally advanced rectal cancer (LARC). XRCC2 was found to be overexpressed in rectal cancer tissues resected from patients who underwent surgery without PRT. In addition, overall survival for LARC patients was improved in XRCC2-negative patients compared with XRCC2-positive patients after treatment with PRT (P < 0.001). XRCC2 expression was also associated with an increase in LARC radioresistance. Conversely, XRCC2-deficient cancer cells were more sensitive to irradiation in vitro, and a higher proportion of these cells underwent cell death induced by G2/M phase arrest and apoptosis. When XRCC2 was knocked down, the repair of DNA double-strand breaks caused by irradiation was impaired. Therefore, XRCC2 may increases LARC radioresistance by repairing DNA double-strand breaks and preventing cancer cell apoptosis. Moreover, the present data suggest that XRCC2 is a useful predictive biomarker of PRT treatment response in LARC patients. Thus, inhibition of XRCC2 expression or activity represents a potential therapeutic strategy for improving PRT response in LARC patients.
BACKGROUND: Epigenetic and genetic alteration plays a major role to the development of head and neck squamous cell carcinoma (HNSCC). Consumption of tobacco (smoking/chewing) and human papilloma virus (HPV) are also associated with an increase the risk of HNSCC. Promoter hypermethylation of the tumor suppression genes is related with transcriptional inactivation and loss of gene expression. We investigated epigenetic alteration (promoter methylation of tumor-related genes/loci) in tumor tissues in the context of genetic alteration, viral infection, and tobacco exposure and survival status.
METHODOLOGY: The study included 116 tissue samples (71 tumor and 45 normal tissues) from the Northeast Indian population. Methylation specific polymerase chain reaction (MSP) was used to determine the methylation status of 10 tumor-related genes/loci (p16, DAPK, RASSF1, BRAC1, GSTP1, ECAD, MLH1, MINT1, MINT2 and MINT31). Polymorphisms of CYP1A1, GST (M1 & T1), XRCC1and XRCC2 genes were studied by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and multiplex-PCR respectively.
PRINCIPAL FINDINGS: Unsupervised hierarchical clustering analysis based on methylation pattern had identified two tumor clusters, which significantly differ by CpG island methylator phenotype (CIMP), tobacco, GSTM1, CYP1A1, HPV and survival status. Analyzing methylation of genes/loci individually, we have found significant higher methylation of DAPK, RASSF1, p16 and MINT31 genes (P = 0.031, 0.013, 0.031 and 0.015 respectively) in HPV (+) cases compared to HPV (-). Furthermore, a CIMP-high and Cluster-1 characteristic was also associated with poor survival.
CONCLUSIONS: Promoter methylation profiles reflecting a correlation with tobacco, HPV, survival status and genetic alteration and may act as a marker to determine subtypes and patient outcome in HNSCC.
Michalska MM, Samulak D, Bieńkiewicz J, et al.Association between -41657C/T single nucleotide polymorphism of DNA repair gene XRCC2 and endometrial cancer risk in Polish women.
Pol J Pathol. 2015; 66(1):67-71 [PubMed
] Related Publications
AIM OF THE STUDY: The XRCC2 gene plays a crucial role in double-strand DNA break repair by homologous recombination. Current literature provides clear evidence that XRCC2 polymorphisms may be associated with the development of certain types of cancer; however, still little is known about their association with endometrial cancer (EC).
MATERIAL AND METHODS: The single nucleotide polymorphism (SNP) -41657C/T (rs718282) of the XRCC2 gene was investigated by PCR-RFLP in 304 patients with EC and in 200 age- and sex-matched non-cancer controls.
RESULTS: The analysis revealed a relationship between XRCC2 -41657C/T polymorphism and the incidence of EC. Endometrial cancer patients showed overrepresentation of the T allele of the SNP. The T/T homozygous variant increased the cancer risk. There were no significant differences between the distribution of XRCC2 -41657C/T genotypes in the subgroups according to histological grade.
CONCLUSIONS: This is the first study that links the SNP -41657C/T (rs718282) of the XRCC2 gene with EC in Polish women. The results support the hypothesis that this polymorphism may be positively correlated with the incidence of EC.
Yang CH, Lin YD, Yen CY, et al.A systematic gene-gene and gene-environment interaction analysis of DNA repair genes XRCC1, XRCC2, XRCC3, XRCC4, and oral cancer risk.
OMICS. 2015; 19(4):238-47 [PubMed
] Related Publications
Oral cancer is the sixth most common cancer worldwide with a high mortality rate. Biomarkers that anticipate susceptibility, prognosis, or response to treatments are much needed. Oral cancer is a polygenic disease involving complex interactions among genetic and environmental factors, which require multifaceted analyses. Here, we examined in a dataset of 103 oral cancer cases and 98 controls from Taiwan the association between oral cancer risk and the DNA repair genes X-ray repair cross-complementing group (XRCCs) 1-4, and the environmental factors of smoking, alcohol drinking, and betel quid (BQ) chewing. We employed logistic regression, multifactor dimensionality reduction (MDR), and hierarchical interaction graphs for analyzing gene-gene (G×G) and gene-environment (G×E) interactions. We identified a significantly elevated risk of the XRCC2 rs2040639 heterozygous variant among smokers [adjusted odds ratio (OR) 3.7, 95% confidence interval (CI)=1.1-12.1] and alcohol drinkers [adjusted OR=5.7, 95% CI=1.4-23.2]. The best two-factor based G×G interaction of oral cancer included the XRCC1 rs1799782 and XRCC2 rs2040639 [OR=3.13, 95% CI=1.66-6.13]. For the G×E interaction, the estimated OR of oral cancer for two (drinking-BQ chewing), three (XRCC1-XRCC2-BQ chewing), four (XRCC1-XRCC2-age-BQ chewing), and five factors (XRCC1-XRCC2-age-drinking-BQ chewing) were 32.9 [95% CI=14.1-76.9], 31.0 [95% CI=14.0-64.7], 49.8 [95% CI=21.0-117.7] and 82.9 [95% CI=31.0-221.5], respectively. Taken together, the genotypes of XRCC1 rs1799782 and XRCC2 rs2040639 DNA repair genes appear to be significantly associated with oral cancer. These were enhanced by exposure to certain environmental factors. The observations presented here warrant further research in larger study samples to examine their relevance for routine clinical care in oncology.
Michalska MM, Samulak D, Romanowicz H, Smolarz BSingle Nucleotide Polymorphisms (SNPs) of RAD51-G172T and XRCC2-41657C/T Homologous Recombination Repair Genes and the Risk of Triple- Negative Breast Cancer in Polish Women.
Pathol Oncol Res. 2015; 21(4):935-40 [PubMed
] Free Access to Full Article Related Publications
Double strand DNA breaks are the most dangerous DNA damage which, if non-repaired or misrepaired, may result in genomic instability, cancer transformation or cell death. RAD51 and XRCC2 encode proteins that are important for the repair of double-strand DNA breaks by homologous recombination. Therefore, genetic variability in these genes may contribute to the occurrence and progression of triple-negative breast cancer. The polymorphisms of the XRCC2 gene -41657C/T (rs718282) and of the RAD51 gene, -172G/T (rs1801321), were investigated by PCR-RFLP in 70 patients with triple-negative breast cancer and 70 age- and sex matched non-cancer controls. The obtained results demonstrated a significant positive association between the RAD51 T/T genotype and TNBC, with an adjusted odds ratio (OR) of 4.94 (p = 0.001). The homozygous T/T genotype was found in 60 % of TNBC cases and in 14 % of the used controls. Variant 172 T allele of RAD51 increased cancer risk (OR = 2.81 (1.72-4.58), p < .0001). No significant associations were observed between -41657C/T genotype of XRCC2 and the incidence of TNBC. There were no significant differences between the distribution of XRCC2 -41657C/T genotypes in the subgroups assigned to histological grades. The obtained results indicate that the polymorphism of RAD51, but not of XRCC2 gene, may be positively associated with the incidence of triple-negative breast carcinoma in the population of Polish women.
Testicular germ cell tumours (TGCTs) are the most common cancer in young men. Here we perform whole-exome sequencing (WES) of 42 TGCTs to comprehensively study the cancer's mutational profile. The mutation rate is uniformly low in all of the tumours (mean 0.5 mutations per Mb) as compared with common cancers, consistent with the embryological origin of TGCT. In addition to expected copy number gain of chromosome 12p and mutation of KIT, we identify recurrent mutations in the tumour suppressor gene CDC27 (11.9%). Copy number analysis reveals recurring amplification of the spermatocyte development gene FSIP2 (15.3%) and a 0.4 Mb region at Xq28 (15.3%). Two treatment-refractory patients are shown to harbour XRCC2 mutations, a gene strongly implicated in defining cisplatin resistance. Our findings provide further insights into genes involved in the development and progression of TGCT.
Qureshi Z, Mahjabeen I, Baig R, Kayani MCorrelation between selected XRCC2, XRCC3 and RAD51 gene polymorphisms and primary breast cancer in women in Pakistan.
Asian Pac J Cancer Prev. 2014; 15(23):10225-9 [PubMed
] Related Publications
Genetic polymorphisms in homologous recombination repair genes cause an abnormal development of cancerous cells. In the present study we evaluated the possibility of breast cancer association with single nucleotide polymorphisms of RAD51, XRCC2 and XRCC3 genes. Polymorphisms selected in this study were RAD51 135G/C, XRCC2 Arg188His; and XRCC3 Thr241Met. Each polymorphism was genotyped using Polymerase chain reaction-restriction fragment length polymorphism in study cohort of 306 females (156 breast cancer patients and 150 controls). We observed that heterozygous variant genotype (GC) of RAD51 135 G/C polymorphism was associated with a significantly (OR=2.70; 95%CI (0.63-1.79); p<0.03) increased risk of breast cancer. In case of the XRCC3 gene we observed that frequency of heterozygous (OR=2.88; 95%CI (1.02-8.14); p<0.02) and homozygous (OR=1.46; 95%CI (0.89-2.40); p<0.04) genotype of Thr241Met polymorphism were significantly higher in breast cancer patients. For the Arg188His polymorphism of XRCC2, ~2fold increase in breast cancer risk (OR=1.6, 95%CI = 0.73-3.50) was associated with GA genotype with a p value for trend of 0.03. Our results suggest that the 135G/C polymorphism of the RAD51, Thr241Met polymorphism of XRCC3 and Arg188His polymorphism of XRCC2 can be independent markers of breast cancer risk in Pakistan.
Shadrina AS, Ermolenko NA, Boyarskikh UA, et al.Polymorphisms in DNA repair genes and breast cancer risk in Russian population: a case-control study.
Clin Exp Med. 2016; 16(1):21-8 [PubMed
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Genetic variation in DNA repair genes can alter an individual's capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians.
X-ray repair complementing defective repair in Chinese hamster cells 2 (XRCC2) and poly(ADP-ribose) polymerase 1 (PARP1) both play important roles in homologous recombination DNA repair. According to the theory of synthetic lethality, XRCC2-deficient cells are more sensitive to PARP1 inhibitors compared to XRCC2-expressing cells. We investigated XRCC2 expression and function in colorectal cancer (CRC), and the characteristics of sensitivity to PARP1 inhibitor in CRC cells with different XRCC2 levels. We enrolled 153 patients with CRC who had undergone surgery in this study. XRCC2 expression was assessed using immunohistochemistry. Stable CRC SW480 cell lines with low or high XRCC2 expression were constructed. Following treatment with the PARP1 inhibitor olaparib, the viability of cells with different XRCC2 levels was determined; cell cycle distribution and apoptosis were analyzed using flow cytometry. B-cell lymphoma-2 (Bcl-2) protein expression was measured by Western blotting. The positive rates of XRCC2 in primary CRC tissue were significantly higher than that in the matched adjacent noncancerous tissue, and XRCC2 expression status in primary CRC was related to tumor site, Dukes' stage, and tumor-nodes-metastasis (TNM) stage. XRCC2 overexpression inhibited CRC cell apoptosis and promoted proliferation by enriching cells in the G0/G1 phase. Moreover, olaparib suppressed proliferation, and olaparib sensitivity in CRC cells with high XRCC2 expression was greater. High XRCC2 expression promotes CRC cell proliferation and enriches cells in the G0/G1 phase but inhibits apoptosis. High XRCC2 expression cells are more sensitive to olaparib, which inhibits their viability.
We studied the prevalence of polymorphisms in genes XRCC2 and XRCC3 in stomach cancer patients who lived in North Eastern Turkey. A total of 61 cancer patients and 78 controls were included in this study. Single nucleotide changes were studied in XRCC2 and XRCC3 genes at locus Arg188His and Thr241Met. Blood samples were taken from the patients and controls, and DNA was isolated. The regions of interest were amplified using a polymerase chain reaction method. After amplification, we used restriction enzymes (HphI and NcoI) to digest the amplified product. Digested product was then run through gel electrophoresis. We identified changes in the nucleotides in these specific regions. It was found that the Arg188His polymorphism of the XRCC2 gene was about 39% (24 out of the 61) among cancer patients. However, only 15% (12 out of 78) of the control group indicated this polymorphism. We also observed that 18 of the 61 cancer patients (29%) carried the Thr241Met polymorphism of the XRCC3 gene whereas 11 of the 78 (14%) individuals in the control group had the polymorphism. Our results showed a significant difference in polymorphism ratios between the cancer patients and health control group for the regions of interest. This result clearly showed that these polymorphisms increase the risk of stomach cancer and might be a strong marker for early diagnosis of gastric cancer.
Oji Y, Tatsumi N, Kobayashi J, et al.Wilms' tumor gene WT1 promotes homologous recombination-mediated DNA damage repair.
Mol Carcinog. 2015; 54(12):1758-71 [PubMed
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The Wilms' tumor gene WT1 is overexpressed in leukemia and various types of solid tumors and plays an oncogenic role in these malignancies. Alternative splicing at two sites yields four major isoforms, 17AA(+)KTS(+), 17AA(+)KTS(-), 17AA(-)KTS(+), and 17AA(-)KTS(-), and all the isoforms are expressed in the malignancies. However, among the four isoforms, function of WT1[17AA(-)KTS(+)] isoform still remains undetermined. In the present study, we showed that forced expression of WT1[17AA(-)KTS(+)] isoform significantly inhibited apoptosis by DNA-damaging agents such as Doxorubicin, Mitomycin, Camptothesisn, and Bleomycin in immortalized fibroblast MRC5SV and cervical cancer HeLa cells. Knockdown of Rad51, an essential factor for homologous recombination (HR)-mediated DNA repair canceled the resistance to Doxorubicin induced by WT1[17AA(-)KTS(+)] isoform. GFP recombination assay showed that WT1[17AA(-)KTS(+)] isoform alone promoted HR, but that three other WT1 isoforms did not. WT1[17AA(-)KTS(+)] isoform significantly upregulated the expression of HR genes, XRCC2, Rad51D, and Rad54. Knockdown of XRCC2, Rad51D, and Rad54 inhibited the HR activity and canceled resistance to Doxorubicin in MRC5SV cells with forced expression of WT1[17AA(-)KTS(+)] isoform. Furthermore, chromatin immunoprecipitation (ChIP) assay showed the binding of WT1[17AA(-)KTS(+)] isoform protein to promoters of XRCC2 and Rad51D. Immunohistochemical study showed that Rad54 and XRCC2 proteins were highly expressed in the majority of non-small-cell lung cancer (NSCLC) and gastric cancer, and that expression of these two proteins was significantly correlated with that of WT1 protein in NSCLCs. Our results presented here showed that WT1[17AA(-)KTS(+)] isoform had a function to promote HR-mediated DNA repair.
Michalska MM, Samulak D, Smolarz BAn association between the -41657 C/T polymorphism of X-ray repair cross-complementing 2 (XRCC2) gene and ovarian cancer.
Med Oncol. 2014; 31(12):300 [PubMed
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X-ray repair cross-complementing group 2 (XRCC2) gene is important for the repair of double-strand DNA breaks (DSB) by homologous recombination (HR). XRCC2 polymorphisms may be associated with the development of certain types of cancers, but little is known about their association with ovarian carcinoma. XRCC2 -41657C/T (rs718282) polymorphisms were genotyped by the PCR-RFLP (restriction fragment length polymorphism) method in 608 patients with ovarian cancer and in 400 cancer-free women, who served as controls. In the present work, a relationship was identified between XRCC2 -41657C/T polymorphism and the incidence of ovarian cancer. An association was observed between ovarian carcinoma occurrence and the presence of T/T genotype [OR = 3.50 (2.46-4.97), p < 0.0001]. A tendency for an increased risk of ovarian cancer was detected with the occurrence of T allele of XRCC2 polymorphism. There were no significant differences between the distribution of XRCC2 -41657C/T genotypes in the subgroups assigned to histological grades. We suggest that the -41657C/T polymorphism of the XRCC2 gene may be risk factors for ovarian cancer development.
Li XB, Luo H, Huang J, et al.XRCC2 gene polymorphisms and its protein are associated with colorectal cancer susceptibility in Chinese Han population.
Med Oncol. 2014; 31(11):245 [PubMed
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XRCC2 is an essential part of the homologous recombination repair pathway. However, relatively little is known about the effect of XRCC2 gene C41657T and G4234C polymorphisms on the individual susceptibility to colorectal cancer (CRC). The purpose of this study was to investigate the association between XRCC2 gene C41657T and G4234C polymorphisms and CRC and to explore the relationship among the polymorphisms and clinicopathologic parameters and protein expression levels of XRCC2. A hospital-based case-control study was conducted with 246 CRC cases and 262 healthy controls. The genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. XRCC2 protein was analyzed by immunohistochemistry for the paraffin sections of 120 CRC cases. The study data showed that the C41657T genotypes were associated with the risk of CRC. The CT/TT genotypes and T allele were overrepresented among the CRC cases. Compared with CC, CT/TT enhanced the risk of CRC (odds ratio = 1.646, 95 % confidence interval = 1.127-2.404, P = 0.010). XRCC2 protein expression of CRC patients with CT/TT genotypes was significantly higher than that of the patients with CC genotype (χ (2) = 4.887, P = 0.027). XRCC2 gene G4234C polymorphisms have no relevance to the risk of CRC. Our findings suggest that XRCC2 C41657T polymorphism may adjust the XRCC2 expression and might influence susceptibility of CRC.
Bashir N, Sana S, Mahjabeen I, Kayani MAAssociation of reduced XRCC2 expression with lymph node metastasis in breast cancer tissues.
Fam Cancer. 2014; 13(4):611-7 [PubMed
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The main purpose of this study was to evaluate the association between reduction in XRCC2 gene and involvement of lymph node metastasis in breast cancer. In first part of the study, meta-analysis of 14 published XRCC2 studies was performed to define the role of XRCC2 gene as diagnostic marker and in second part of the study XRCC2 gene expression was observed using real time PCR in study cohort of 100 females (50 breast cancer patients and 50 controls). A statistically significant down regulation of XRCC2 (p < 0.04) and up-regulation of ki-67 (p < 0.05) was observed in breast cancer tissues compared to non-cancerous healthy tissues. In order to explore gene-gene and gene-clinicopathological parameters relationship Spearmen correlation was performed. We observed a significantly negative correlation between XRCC2 and Ki-67 expression (r = -0.376**, p < 0.01). In case of gene-clinicopathological parameters relationship, we observed a significant correlation between XRCC2 expression and lymph node status (r = -0.521***, p < 0.002) and metastatic status (r = -0.303*, p < 0.04) of breast cancer patients. Our data suggests that deregulation of XRCC2 in breast cancer has the potential to predict lymph node metastasis and may serve as a therapeutic target for breast cancer patients at risk of metastasis.
Sullivan I, Salazar J, Majem M, et al.Pharmacogenetics of the DNA repair pathways in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy.
Cancer Lett. 2014; 353(2):160-6 [PubMed
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Genetic variants in DNA repair genes may play a role in the effectiveness of platinum-based chemotherapy in non-small cell lung cancer (NSCLC). We analyzed 17 SNPs in eight genes (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, XPA, XRCC1 and XRCC2) involved in DNA repair mechanisms and its association with outcome in NSCLC. This prospective study included patients with stages III and IV treated with platinum-based chemotherapy. All patients (n = 161) received cisplatin or carboplatin plus a third-generation drug. Additionally, stage IIIA and IIIB patients (n = 74) received concomitant or sequential radiotherapy. Germline polymorphisms were analyzed using the BioMark system in blood DNA samples. We found that in stage III patients, response was significantly associated with SNPs in ERCC1 and in ERCC3 genes, while radiotherapy-derived toxicity correlated with SNPs in the ERCC2 gene. In stage IV patients, response was associated with a genetic variant in the ERCC4 gene and survival with a SNP in the XRCC1 gene. The complexity of the DNA repair mechanisms along with the heterogeneity in the treatment of lung cancer could explain the role of multiple genes as putative biomarkers of patient outcome.
Choudhury JH, Choudhury B, Kundu S, Ghosh SKCombined effect of tobacco and DNA repair genes polymorphisms of XRCC1 and XRCC2 influence high risk of head and neck squamous cell carcinoma in northeast Indian population.
Med Oncol. 2014; 31(8):67 [PubMed
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Tobacco consumption in various forms is one of the major risk factor for the development of head and neck squamous cell carcinoma. Polymorphisms in XRCC1 and XRCC2 genes may alter an individual's susceptibility to tobacco-related cancers. Here, we have investigated the interaction of XRCC1 (Arg399Gln) and XRCC2 (Arg188His) polymorphism and tobacco exposure in the progression of HNSCC in northeast Indian population. The population-based case-control study includes 110 HNSCC patients and 140 controls. The polymorphisms of XRCC1 and XRCC2 were studied by means of PCR-RFLP, and the results were confirmed by DNA sequencing. Smokers and tobacco-betel quid chewers were significantly higher in cases (P = 0.045 and 0.033). The variant homozygote AA genotype of XRCC1 Arg399Gln and heterozygote GA genotype of XRCC2 Arg188His has an increased risk toward HNSCC (OR 2.43; P = 0.031 and OR 3.29; P < 0.01, respectively). The interaction between tobacco-betel quid chewing and variant genotypes of XRCC1 and XRCC2 resulted in several fold increase the risk of HNSCC, when compared to non-chewers. Heavy smokers carrying XRCC1 AA and XRCC2 GA genotypes had a significantly higher risk of HNSCC compared to never smokers (P = 0.017 and 0.003, respectively). Upon gene-gene interaction analysis, individuals carrying both XRCC1 GA (Arg/Gln) and XRCC2 GA (Arg/His) genotypes had the highest risk of HNSCC (P = 0.001).Our finding suggests that interaction of tobacco and polymorphisms of XRCC1 and XRCC2 increases the risk of HNSCC. Furthermore, cross talk between these two DNA repair genes might modulate susceptibility toward HNSCC.
Smolarz B, Makowska M, Samulak D, et al.Association between single nucleotide polymorphisms (SNPs) of XRCC2 and XRCC3 homologous recombination repair genes and triple-negative breast cancer in Polish women.
Clin Exp Med. 2015; 15(2):151-7 [PubMed
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XRCC2 and XRCC3 genes involved in homologous recombination repair (HRR) of DNA and in the maintenance of the genome integrity play a crucial role in protecting against mutations that lead to cancer. The aim of the present work was to evaluate associations between the risk of triple-negative breast cancer (TNBC) and polymorphisms in the genes, encoding for two key proteins of HRR: XRCC2 Arg188His (c. 563 G>A; rs3218536, Genbank Accession Number NT 007914) and XRCC3 Thr241Met (c. 722 C>T; rs861539, Genbank Accession Number NT 026437). The polymorphisms of the XRCC2 and XRCC3 were investigated by PCR-RFLP in 70 patients with TNBC and 70 age- and sex-matched non-cancer controls. In the present work, a relationship was identified between XRCC2 Arg188His polymorphism and the incidence of triple-negative breast cancer. The 188His allele and 188His/His homozygous variant increased cancer risk. An association was confirmed between XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms and TNBC progression, assessed by the degree of lymph node metastases and histological grades. In conclusion, XRCC2 Arg188His and XRCC3 Thr241Met polymorphisms may be regarded as predictive factors of triple-negative breast cancer in female population.
BACKGROUND: Converging evidence supports the central role of DNA damage in progression to breast cancer. We therefore in this study aimed to assess the potential interactions of seven common polymorphisms from five DNA repair genes (XRCC1, XRCC2, XRCC3, XPA and APEX1) in association with breast cancer among Han Chinese women.
METHODOLOGY/PRINCIPAL FINDINGS: This was a case-control study involving 606 patients diagnosed with sporadic breast cancer and 633 age- and ethnicity-matched cancer-free controls. The polymerase chain reaction-ligase detection reaction method was used to determine genotypes. All seven polymorphisms were in accordance with Hardy-Weinberg equilibrium in controls. Differences in the genotypes and alleles of XRCC1 gene rs25487 and XPA gene rs1800975 were statistically significant between patients and controls, even after the Bonferroni correction (P<0.05/7). Accordingly, the risk for breast cancer was remarkably increased for rs25487 (OR = 1.28; 95% CI: 1.07-1.51; P = 0.006), but decreased for rs1800975 (OR = 0.77; 95% CI: 0.67-0.90; P = 0.001) under an additive model at a Bonferroni corrected alpha of 0.05/7. Allele combination analysis showed higher frequencies of the most common combination C-G-G-C-G-G-G (alleles in order of rs1799782, rs25487, rs3218536, rs861539, rs1800975, rs1760944 and rs1130409) in controls than in patients (PSim = 0.002). In further interaction analysis, two-locus model including rs1800975 and rs25487 was deemed as the overall best model with the maximal testing accuracy of 0.654 and the cross-validation consistency of 10 out of 10 (P = 0.001).
CONCLUSION: Our findings provide clear evidence that XRCC1 gene rs25487 and XPA gene rs1800975 might exert both independent and interactive effects on the development of breast cancer among northern Chinese women.
Nakagawa Y, Kajihara A, Takahashi A, et al.The BRCA2 gene is a potential molecular target during 5-fluorouracil therapy in human oral cancer cells.
Oncol Rep. 2014; 31(5):2001-6 [PubMed
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5-Fluorouracil (5-FU) is widely used in clinical cancer therapy. It is commonly used either alone or in combination with other drugs and/or radiation for head and neck, and other types of cancers. 5-FU induces DNA double-strand breaks (DSBs). Inhibition of the repair of 5-FU-induced DSBs may improve the therapeutic response in many tumors to this anticancer agent. The aim of the present study was to further our understanding of the pathways which are involved in the repair of 5-FU-induced DSBs. Cell survival after drug treatment was examined with colony forming assays using Chinese hamster lung fibroblast cells or Chinese hamster ovary cell lines which are deficient in DSB repair pathways involving the homologous recombination repair-related genes BRCA2 and XRCC2, and the non-homologous end joining repair-related genes DNA-PKcs and Ku80. It was found that BRCA2 was involved in such repair, and may be effectively targeted to inhibit the repair of 5-FU-induced damage. Observations showed that knockdown of BRCA2 using small interference RNA suppression increased the sensitivity to 5-FU of human oral cancer cell lines (SAS and HSC3). These findings suggest that downregulation of BRCA2 may be useful for sensitizing tumor cells during 5-FU chemotherapy.
BACKGROUND: Association between the single nucleotide polymorphism rs3218536 (known as Arg188His) located in the X-ray repair cross complementing group 2 (XRCC2) gene and cancer susceptibility has been widely investigated. However, results thus far have remained controversial. A meta-analysis was performed to identify the impact of this polymorphism on cancer susceptibility.
METHODS: PubMed and Embase databases were searched systematically until September 7, 2013 to obtain all the records evaluating the association between the XRCC2 Arg188His polymorphism and the risk of all types of cancers. We used the odds ratio (OR) as measure of effect, and pooled the data in a Mantel-Haenszel weighed random-effects meta-analysis to provide a summary estimate of the impact of this polymorphism on breast cancer, ovarian cancer and other cancers. All the analyses were carried out in STATA 12.0.
RESULTS: With 30868 cases and 38656 controls, a total of 45 case-control studies from 26 publications were eventually included in our meta-analysis. No significant association was observed between the XRCC2 Arg188His polymorphism and breast cancer susceptibility (dominant model: OR = 0.94, 95%CI = 0.86-1.04, P = 0.232). However, a significant impact of this polymorphism was detected on decreased ovarian cancer risk (dominant model: OR = 0.83, 95%CI = 0.73-0.95, P = 0.007). In addition, we found this polymorphism was associated with increased upper aerodigestive tract (UADT) cancer susceptibility (dominant model: OR = 1.51, 95%CI = 1.04-2.20, P = 0.032).
CONCLUSION: The Arg188His polymorphism might play different roles in carcinogenesis of various cancer types. Current evidence did not suggest that this polymorphism was directly associated with breast cancer susceptibility. However, this polymorphism might contribute to decreased gynecological cancer risk and increased UADT cancer risk. More preclinical and epidemiological studies were still imperative for further evaluation.