Valor prognóstico de polimorfismos nos genes de reparo do DNA XRCC3 E RAD51 em pacientes com carcinoma epidermóide oral e de orofaringe / Prognostic value of polymorphisms of DNA repair gene RAD51 XRCC3 and in patients with oral squamous cell carcinoma and oropharyngeal

Falhas nos genes responsáveis por reparos no DNA podem influenciar no surgimento de câncer ou afetar a resposta aos tratamentos. Estudos têm demonstrado que a variação na capacidade de reparo do DNA pode ser resultado de polimorfismos funcionais nestes genes, e alguns destes experimentos sugerem que a presença de polimorfismos de nucleotídeos simples (SNPs), em genes de reparo, está relacionada ao desenvolvimento e resposta ao tratamento de vários cânceres, incluindo o Carcinoma Epidermoide Oral (CEO) e o Carcinoma Epidermoide de Orofaringe (CEOR). Nesta pesquisa avaliou-se a frequência de três SNPs em dois genes de reparo do DNA RAD51 172G>T (c.-61 G>T, rs1801321), RAD51 135G>C (c.-98 G>C, rs1801320) e XRCC3 T241M (c. 722 C>T, rs861539) em indivíduos saudáveis (n=130) e indivíduos com CEO e CEOR (n=126) e investigou-se possíveis relações de tais achados com os desfechos clínicos: resposta tumoral ao tratamento com radioterapia e quimioterapia, recidiva, e sobrevida global. Constatou-se frequência alélica e genotípica em equilíbrio. A presença dos SNPs analisados não revelou ser um fator de risco para o desenvolvimento de CEO ou CEOR; contudo, quando associado ao hábito de fumar ou beber, aumentou o risco de desenvolver o câncer de três a cento e cinquenta vezes (p<000,1). A resposta tumoral ao tratamento de radioterapia e quimioterapia foi semelhante nos pacientes com ou sem SNPs. Nenhum polimorfismo demonstrou significância estatística em relação à sobrevida livre de recidiva ou sobrevida global. Os genótipos AA e AC do SNP rs861539 no gene XRCC3, os genótipos CC e CG do SNP rs1801320 e GG e GT do SNP 1801321 no gene RAD51, aumentam o risco do desenvolvimento de carcinoma epidermoide oral e de orofaringe, quando associados ao hábito de beber ou fumar. Os polimorfismos estudados nos genes XRCC3 e RAD51 não estão associados à resposta à radioterapia, sobrevida livre de recidiva ou sobrevida global

Faults in the genes responsible for repairs to the DNA can influence the onset of cancer or affect the response to treatment. This research evaluated the frequency of three single nucleotide polymorphisms (SNPs) in two repair genes DNA RAD51 172g> T (rs1801321), RAD51 135G> C (rs1801320) and XRCC3 T241M (rs861539) in individuals without cancer (n = 130) and patients with oral squamous cell carcinoma (OSC) and carcinoma oropharyngeal squamous (ORSC) (n = 126) and investigated possible relationships of these findings with clinical and pathological data and clinical outcomes: tumor response to radiotherapy and chemotherapy, disease-free survival, and overall survival. It was found that the allele and genotype frequencies were in equilibrium Hard-Weinberg equilibrium. The presence of at least one polymorphic allele in XRCC3 (rs861539) gene is associated with histological grade (WHO) higher (p = 0.007). We observed a higher recurrence rate trend (p = 0.08) and more advanced stage (p = 0.08) in the group that had at least one polymorphic allele of RAD51 gene (rs1801321). The presence of the analyzed SNPs not proved to be a risk factor for the development of CEO or CEOR; however, when combined with smoking or drinking, increased the risk of developing cancer from three to one hundred and fifty times. The tumor response to radiotherapy and chemotherapy was similar in patients with and without SNPs. No polymorphism showed statistical significance in relation to recurrence-free survival or overall survival. We conclude that the presence of at least one polymorphic allele of the SNPs rs861539 in XRCC3 gene, rs1801320 and rs1801321 in the RAD51 gene increase the risk of development of OSC and ORSC, when associated with the habit of drinking or smoking. Polymorphisms studied in XRCC3 and RAD51 genes are not associated with response to radiation therapy, relapse-free survival or overall survival

Association between XRCC3 Thr241Met Polymorphism and the Risk of Cancer in Northern Brazil.

Aims: Cancer is a genetic disease characterized by an unbalance between cell growth and regulatory factors. The gene XRCC3 encodes a protein that contributes to the integrity of the genome and XRCC3 Thr241Met variants have their capacity of repair altered. Study Design: Our goal was to evaluate XRCC3 241Met polymorphism in a sample of cancer patients in the city of Macapá. Place and Duration of Study: Laboratory of Molecular Biology (Biological Sciences Program of the Federal University of Amapá), Dr. Alberto Lima Clinical Hospital (Hcal) and Institute of Hematology and Hemotherapy of Amapá between June 2009 and July 2010. Methodology: We analyzed 100 DNA samples of patients (50 cases diagnosed with cancer and 50 controls). DNA samples were amplified and analyzed by PCR-RFLP with the enzyme NLaIII. Results: The molecular analysis revealed that 58% of cases and 12% of controls had the Thr/Met genotype, while 82% of controls and 36% of cases had the Thr/Thr genotype. Conclusion: Non-invasive independent predictors for screening esophageal varices may decrease medical as well as financial burden, hence improving the management of cirrhotic patients. These predictors, however, need further work to validate reliability. The frequency of the Thr/Met genotype was higher among cancer patients when compared to the control group. Our findings suggest that XRCC3 241Met polymorphism may be associated with the risk cancer in the study population.

Effects and underlying mechanisms of homologous recombina-tion-associated protein XRCC3 on esophageal squamous-cell carci-noma radiotherapy response / 中国肿瘤临床

Objective:To investigate the effects and underlying mechanisms of XRCC3 on esophageal squamous-cell carcinoma (ESCC) radiotherapy response. Methods:Expression levels of XRCC3 were detected by reverse transcription PCR, Western blot, and immunohistochemistry. We knocked down XRCC3 with lentiviral infection in ESCC cells. Cell apoptosis was examined by flow cytom-etry. DNA damage and telomere dysfunction-induced foci were determined by immunofluorescence. Results:The expression levels of XRCC3 in ESCC cells and tissues were higher than those in normal esophageal epithelial cells and corresponding adjacent noncancer-ous esophageal tissues. Knockdown of XRCC3 in ESCC cells substantially increased the therapeutic efficacy of radiation. We demon-strated that the radiation resistance of XRCC3 was attributed to the XRCC3-maintaining telomere stability, which reduced ESCC cell death through radiation-induced apoptosis. Conclusion: Our data suggested that XRCC3 protects ESCC cells from ionizing radia-tion-induced DNA damage and death by enhancing telomere stability. Thus, XRCC3 can be used as a promising therapeutic target for ESCCs.

Meta analysis of XRCC3 Thr241Met polymorphism and lung cancer susceptibility of populations in East Asia

OBJECTIVE@#To assess the relation between XRCC3 Thr241Met polymorphism and lung cancer susceptibility of populations in East Asia.@*METHODS@#Related studies of XRCC3 Thr241Met polymorphism and lung cancer susceptibility of populations in East Asia were collected through searching the Pubmed, Embase Library, SPRINGER, CNKI and CSSCI.@*RESULTS@#According to the entry criteria, there were 8 case-control studies in the assessing system and there were 6 321 study cases, including 3 215 patients with lung cancer and 3 106 cases without cancers. Meta analysis results showed the combined OR value of the ratio of genotype Thr/Met+Met/Met and Thr/Thr was 1.03 (95%CI: 0.89-1.20) (P>0.05).@*CONCLUSIONS@#XRCC3 Thr241Met polymorphism may not related to lung cancer susceptibility of populations in East Asia. Allele 241Met did not increase the risk of lung cancer.

Avaliação de polimorfismos nos genes XPD e XRCC3 em carcinomas orais de células escamosas / Evaluation of polymorphisms in the XPD and XRCC3 genes in oral squamous cell carcinomas

O carcinoma oral de células escamosas (COCE) é importante causa de morbidade e mortalidade em todo o mundo a despeito dos recentes avanços nas formas de tratamento. Diante disto, várias são as pesquisas no intuito de se encontrar marcadores que possam melhorar a avaliação do prognóstico desta doença. Neste sentido têm se destacado os estudos dos polimorfismos genéticos, os quais podem influenciar a suscetibilidade individual para o desenvolvimento do câncer. O objetivo deste estudo foi avaliar a associação entre a frequência dos polimorfismos XPD Lys751Gln e XRCC3 Thr241Met e o perfil clinicopatológico em casos de COCE, incluindo idade, sexo, presença ou não de metástase e gradação histológica de malignidade de Bryne (1998). A amostra foi composta por 54 casos de COCE e 40 casos de hiperplasia fibrosa inflamatória (HFI). Os casos de COCE foram classificados como lesões de baixo ou de alto grau de malignidade. Foram utilizadas amostras de DNA previamente extraído de blocos de parafina. Os genótipos para cada caso foram determinados através da técnica de PCR-RFLP (reação em cadeia da polimerase - polimorfismos de comprimento de fragmentos de restrição). Os resultados foram submetidos aos testes estatísticos Exato de Fisher e Quiquadrado de Pearson e foi calculada a razão de chance (odds ratio) considerando o nível de significância quando p<0,05. Para o XPD, o genótipo Lys/Gln foi mais comum nas HFIs (n=28; 70%) que nos COCEs (n=24; 44,4%) (OR: 0,3; p<0,05). A frequência do alelo Gln foi maior nas lesões de alto grau, em comparação às de baixo grau (0,48 e 0,21, respectivamente) (OR: 3,4; p<0,05). Para o XRCC3, o alelo Met foi mais frequente no COCE que na HFI (0,49 e 0,35, respectivamente) (OR: 2,6; p<0,05). O genótipo Met/Met foi associado à presença de metástases (OR: 8,1; p<0,05). Não houve associação estatística significativa entre os genótipos e a idade ou sexo dos pacientes. Na amostra analisada, a maior frequência do alelo XPD Gln na HIF revela um possível papel protetor dessa variante contra o desenvolvimento do COCE. Todavia, sua associação com lesões de alto grau, indica que esse alelo poderia influenciar no processo de progressão após o tumor instalado. A presença do alelo XRCC3 Met, por sua vez, parece contribuir com o desenvolvimento do COCE e de metástases nessas lesões. (AU)

Oral squamous cell carcinoma (OSCC) is an important cause of morbidity and mortality worldwide despite recent advances in treatment. There are several studies aiming to find markers that may improve the assessment of this disease prognosis. Studies about genetic polymorphisms have gained prominence due to their influence on individual susceptibility to cancer development. The aim of this study was to evaluate the association between the frequency of polymorphisms XPD Lys751Gln and XRCC3 Thr241Met and clinicopathological features of OSCC cases, including age, sex, presence or absence of metastases, and histological grading of malignancy according to Bryne (1998). Sample consisted of 54 cases of OSCC and 40 cases of inflammatory fibrous hyperplasia (IFH). OSCC cases were classified as low or high grade. DNA samples were previously extracted from paraffin blocks. Genotypes for each case were determined through PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism). Results were analyzed by Fisher's exact test and Chi-square test and the odds ratio was calculated considering p < 0.05 to indicate statistical significance. For XPD, Lys/Gln genotype was more common in IFHs (n=28; 70%) than in OSCCs (n=24; 44.4%) (OR: 0.3; p<0.05). Frequency of Gln allele was higher in high-grade lesions when compared to low grade lesions (0.48 and 0.21, respectively) (OR: 3.4; p<0.05). For XRCC3, Met allele was more common in OSCC than in IFH (0.49 and 0.35, respectively) (OR: 2.6; p<0.05). Met/Met genotype was associated with presence of metastases (OR: 8.1; p<0.05). There was no statistically significant association between the genotypes and the age or sex of patients. In the present sample, the higher frequency of XPD Gln allele in IFH reveals a possible protective role of this variant against the development of OSCC. However, its association with high-grade lesions indicates that this allele could influence the tumor progression after the neoplasia development. The presence of XRCC3 Met allele, in turn, seems to contribute to the development of OSCC and metastases. (AU)

DNA Repair Genes XRCC1, XRCC3, XPD, and OGG1 Polymorphisms among the Central Region Population of Saudi Arabia

DNA repair is one of the central defense mechanisms against mutagenic exposures. Inherited SNPs of DNA repair genes may contribute to variations in DNA repair capacity and susceptibility to cancer. Due to the presence of these variants, inter-individual and ethnic differences in DNA repair capacity have been established in various populations. Saudi Arabia harbors enormous genetic and cultural diversity. In the present study we aimed to determine the genotype and allele frequencies of XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), XPD Lys751Gln (rs13181), and OGG1 Ser326Cys (rs1052133) gene polymorphisms in 386 healthy individuals residing in the central region of Saudi Arabia and compare them with HapMap and other populations. The genotype and allele frequencies of the four DNA repair gene loci in central Saudi population showed a distinctive pattern. Furthermore, comparison of polymorphisms in these genes with other populations also showed a unique pattern for the central Saudi population. To the best of our knowledge, this is the first report that deals with these DNA repair gene polymorphisms among the central Saudi population.

Association between XRCC3 Thr241Met polymorphism and genetic susceptibility to glioma in Chinese Han population living in Shanghai and surrounding provinces in east China / 第二军医大学学报

Objective: To investigate the possible association between Thr241Met polymorphism in the DNA repair gene X ray repair cross-complementing group 3 (XRCC3) with genetic susceptibility to glioma in a Chinese Han population living it Shanghai and the surrounding provinces in east China. Methods: Genotyping by a TaqMan assay was performed in 771 brain glioma patients living in Shanghai and the surrounding provinces (Jiangsu, Zhejiang, Anhui, etc.) and in 752 control participants matched in age and gender. The genotyping results of TaqMan assay and the association between Thr241Met polymorphism in the DNA repair gene XRCC3 with genetic susceptibility to glioma were statistically analyzed. Results: Genotypes of 1 468 subjects (760 with brain glioma and 708 were cancer-free control) were successfully performed by TaqMan assay, with the successful rate being 96.4%. Statistical analysis result showed that gene(C/T) and genotype (C/C,T/C,T/T) frequencies of XRCC3 were not significantly different between the glioma and cancer-free groups. Compared with the CC genotype, the variant TC(P=O.909; adjusted by age and gender OR=0.981; 95%CI=0.701-1.371) or TT(P=0.642; adjusted by age and gender OR=0.7; 95%CI=0.156-3.146) genotypes of XRCC3 Thr241Met were associated with a non-statistically significant increase of glioma risk. Conclusion: The variant TC or TT genotypes of XRCC3 Thr241Met may not be risk factors for brain glioma it Chinese Han population living in Shanghai and the surrounding provinces in east China.

Association between XRCC3 Thr241Met polymorphism and genetic susceptibility to glioma in Chinese Han population living in Shanghai and surrounding provinces in east China / 第二军医大学学报

Objective:To investigate the possible association between Thr241Met polymorphism in the DNA repair gene X-ray repair cross-complementing group 3 (XRCC3) with genetic susceptibility to glioma in a Chinese Han population living in Shanghai and the surrounding provinces in east China. Methods: Genotyping by a TaqMan assay was performed in 771 brain glioma patients living in Shanghai and the surrounding provinces (Jiangsu.Zhejiang, Anhui.etc. )and in 752 control participants matched in age and gender. The genotyping results of TaqMan assay and the association between Thr241Met polymorphism in the DNA repair gene XRCC3 with genetic susceptibility to glioma were statistically analyzed. Results: Genotypes of 1 468 subjects (760 with brain glioma and 708 were cancer-free control) were successfully performed by TaqMan assay, with the successful rate being 96.4%. Statistical analysis result showed that gene(C/T) and genotype(C/CT/CT/T) frequencies of XRCC3 were not significantly different between the glioma and cancer-free groups. Compared with the CC genotype, the variant TC(P = 0. 909; adjusted by age and gender OR = 0. 981; 95%CI = 0. 701-1. 371) or TT(P=0. 642; adjusted by age and gender OR = 0. 7; 95%CI = 0. 156-3. 146) genotypes of XRCC3 Thr241Met were associated with a non-statistically significant increase of glioma risk. Conclusion: The variant TC or TT genotypes of XRCC3 Thr241Met may not be risk factors for brain glioma in Chinese Han population living in Shanghai and the surrounding provinces in east China.