DNA修复基因XRCC1基因多态性与乳腺癌临床病理参数的相关性

目的 :研究XRCC1基因Arg194Trp和Arg399Gln多态性与中国女性乳腺癌临床病理参数的关系,探讨其在乳腺癌预后中的潜在意义。 方法 :采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法,对250例原发性乳腺癌患者进行XRCC1基因Arg194Trp、Arg399Gln多态性分析,用Pearsonχ²检验分析基因型与临床病理特征的关系。 结果 :XRCC1基因Arg194Trp和Arg399Gln多态性与乳腺癌患者的月经状态、肿瘤大小、腋窝淋巴结转移、TNM分期、雌激素受体均无显著相关性(P>0.05)。但该多态位点与乳腺癌患者的孕激素受体(PR)状态和C-erbB2蛋白表达显著相关。携带194纯合突变型的患者PR阴性率(81.0%)显著高于携带194野生型和杂合型患者(55.4%),(P=0.034);携带399纯合突变型的患者C-erbB2蛋白表达阳性率(61.1%)显著高于携带399野生型和杂合型的患者(29.3%),(P=0.006)。 结论 :PR阴性和(或)C-erbB2高表达的乳腺癌患者常提示预后不良。XRCC1基因多态性与PR阴性或C-erbB2高表达显著相关,提示携带XRCC1纯合突变(194或399)乳腺癌患者可能预后不良。     

MDM2 启动子区309 位点基因多态性与乳腺癌风险的关系*

目的:采用病例- 对照研究检测MDM2 启动子区309 位点T>G 单核苷酸多态（SNP 309）在中国女性人群中的频率分布,分析其与中国女性乳腺癌发病风险的关系。方法:提取病例组698 例原发性乳腺癌患者及对照组525 例健康人的外周血单核细胞DNA,采用聚合酶链反应- 限制性片段长度多态性（PCR-RFLP ）分析法,检测MDM2 启动子区309 位点基因多态性,确定此位点三种基因型,即T/T、T/G、G/G 基因型。统计分析病例组和对照组人群MDM2 SNP 309 各基因型频率分布,及各基因型与乳腺癌发病风险的相关性。结果:在研究的病例组与对照组整体人群中,经年龄、月经状态、家族史及生育史等因素校正后,与MDM2 SNP 309 T/T基因型比较,T/G 型及G/G 型与乳腺癌的发病风险无显著相关性（T/G,adjusted OR= 1.2,95%CI:0.8～1.6,P=0.30;G/G,adjusted OR= 1.0,95%CI:0.7～1.5,P=0.88）。 进一步分层分析后显示:在绝经后人群中,与T/T基因型比较,T/G 基因型及G/G 基因型显著增加乳腺癌的发病风险（T/G,adjusted OR= 1.8,95%CI:1.2～3.0,P=0.011;G/G,adjusted OR= 1.9,95%CI:1.2～3.3,P=0.014）。 提示绝经后人群携带T/G 型、G/G 型者比携带T/T基因型者患乳腺癌的风险分别升高约1.8、1.9 倍。在绝经前人群中,各基因型与乳腺癌的发病风险无显著相关性（P>0.05）。 结论:MDM2 启动子309 位点突变型G 等位基因携带者显著增加绝经后女性乳腺癌的发病风险。      

Case-Control Study on the Fibroblast Growth Factor Receptor 2 Gene Polymorphisms Associated with Breast Cancer in Chinese Han Women

Purpose

Genetic variation in fibroblast growth factor receptor 2 (FGFR2) is a newly described risk factor for breast cancer. This study aimed to evaluate the association of four single nucleotide polymorphisms (SNPs) in FGFR2 with breast cancer in Han Chinese women.

Methods

Two hundred three women with breast cancer and 200 breast cancer-free age-matched controls were selected. Four SNPs (rs2981579, rs1219648, rs2420946, and rs2981582) and their haplotypes were analyzed to test for their association with breast cancer susceptibility. The presence of the four FGFR2 SNPs was determined by polymerase chain reaction-restriction fragment length polymorphism analysis.

Results

A statistically significant difference was observed in the frequency of rs2981582 in the FGFR2 gene (p<0.05) between case and control groups. In subjects stratified by menopausal status, rs2981582 TT, rs2420946 AA, and rs1219648 CC were significantly associated with the risk of breast cancer in postmenopausal subjects, but no significant associations between these four SNPs and the risk of breast cancer were identified in premenopausal subjects. Further, there was no significant association between hormone receptor status (estrogen receptor and progesterone receptor) and breast cancer risk. Six common (> 3%) haplotypes were identified. Three of these haplotypes, CGTC (odds ratio [OR], 0.613; 95% confidence interval [CI], 0.457-0.82; p=0.001), TGTC (OR, 6.561; 95% CI, 2.064-20.854; p<0.001), and CATC (OR, 12.645; 95% CI, 1.742-91.799; p=0.001) were significantly associated with breast cancer risk.

Conclusion

Our findings indicated that the SNP rs2981582 and haplotypes CGTC, TGTC, and CATC in FGFR2 may be associated with an increased risk of breast cancer in Han Chinese women.     

Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms and Breast Cancer Risk in a Chinese Population

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in thedevelopment and progression of solid tumours. Associations between three VEGF gene polymorphisms (-634G/C, +936 C/T, and +1612 G/A) and breast cancer risk have been extensively studied, but the currently availableresults are inconclusive. Our aim was to investigate associations between three VEGF gene polymorphisms andbreast cancer risk in Chinese Han patients. We performed a hospital-based case-control study including 680female incident breast cancer patients and 680 female age-matched healthy control subjects. Polymerase chainreaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect the threeVEGF gene polymorphisms. We observed that women carriers of +936 TT genotypes [odds ratio (OR) =0.46,95% confidence interval (CI) = 0.28, 0.76; P=0.002] or 936 T-allele (OR=0.81, 95% CI= 0.68, 0.98; P=0.03) hada protective effect concerning the disease. Our study suggested that the +1612G/A polymorphism was unlikelyto be associated with breast cancer risk. The -634CC genotype was significantly associated with high tumoraggressiveness [large tumor size (OR=2.63, 95% CI=1.15, 6.02; P=0.02) and high histologic grade (OR=1.47,95% CI= 1.06, 2.03; P=0.02)]. The genotypes were not related with other tumor characteristics such as regionalor distant metastasis, stage at diagnosis, or estrogen or progesterone receptor status. Our study revealed thatthe VEGF -634 G/C and +936 C/T gene polymorphisms may be associated with breast cancer in Chinese Hanpatients.     

IFN-γ基因+874位点单核苷酸多态性与乳腺癌的相关性

 目的探讨IFN-γ基因+874位点单核苷酸多态性与乳腺癌的相关性。方法采用PCR技术对94例乳腺癌患者及96例正常女性IFN-γ基因+874位点A/T单核苷酸多态性(SNP)进行分析,将PCR产物进行克隆、测序。结果乳腺癌患者IFN-γ基因+874位点TT基因型频率为18.1%,显著高于正常人的8.3%,两者之间比较具有显著性差异(χ²=3.95,P=0.047);乳腺癌病例组T等位基因频率显著高于对照组(χ²=4.984,P=0.026)。进一步分析显示,乳腺癌病例组中不同年龄段基因型频率和等位基因频率相比,均无显著性差异。结论IFN-γ基因+874位点TT基因型可能与乳腺癌的发生相关,T等位基因可能为乳腺癌发生的遗传危险因素。     

TNRC9 基因 rs12443621多态与中国人乳腺癌的相关性

 目的 探讨TNRC9 基因 rs12443621多态与中国妇女乳腺癌易感性及临床病理特征的关系。 方法 抽取321例乳腺癌患者和330例健康对照外周血,分离淋巴细胞,抽提基因组DNA,采用聚合酶链反应 连接酶检测反应(PCR-LDR)检测TNRC9 rs12443621基因多态,比较基因型分布和发病风险及临床病理特征的关系。危险度比值比(OR)及95％可信区间(CI)应用非条件Logistic回归分析计算。结果 Rs12443621 GG、AG和 AA基因型在病例组和对照组分别为 35.6%、46.3%、18.1%和 33.1%、48.1%、18.8%。 TNRC9 rs12443621基因型与发病年龄、淋巴结转移情况及雌、孕激素状态均无相关性。结论 TNRC9基因rs12443621多态与中国妇女乳腺癌易感性及临床病理特征无相关性。     

CASC15 Polymorphisms are Correlated With Breast Cancer Susceptibility in Chinese Han Women

IntroductionBreast cancer (BC) is a prevalent malignant tumor among women. Numerous studies have been reported that long noncoding RNAs (lncRNAs) were associated with various human diseases.Materials and MethodsIn the current study, 681 patients with BC and 680 unrelated controls were recruited to investigate the correlation between lncRNA cancer susceptibility candidate 15 (CASC15) polymorphisms and BC risk in Chinese Han women. We performed single-nucleotide polymorphism genotyping using the Agena MassARRAY platform. The relationship between lncRNA CASC15 polymorphisms and the risk of BC were evaluated through odds ratios and 95% confidence intervals.ResultsOur results suggested that the lncRNA CASC15 rs7740084 “G/G” genotype and rs1928168 “T/C” genotype significantly reduced BC risk in different genetic models (P = .045, P = .029, and P = .047, respectively). However, rs9393266 “C/T” and “C/T-T/T” genotypes were correlated with the risk of BC (P = .021 and P = .048). In addition, we also observed that rs1928168 was related to the risk of BC in patients with age > 50 years (P = .025), body mass index > 24 (P = .006), and tumor size (P = .035). For rs9393266, it was revealed that the “C/T” and “C/T-T/T” genotypes were related to BC risk in people with age ≤ 50 years (P = .005) and body mass index > 24 (P = .023).ConclusionIn summary, our results revealed a potential interaction between lncRNA CASC15 polymorphisms and BC susceptibility. The results provided an important insight into lncRNA CASC15 function in the development of BC.     

贵州汉族人群乳腺癌与FGFR2 rs1219648多态性相关性研究*

目的：探讨贵州汉族人群成纤维细胞生长因子受体2（fibroblast growth factor receptor 2,FGFR2）基因单核苷酸多态性与女性乳腺癌易感性之间的相关性。方法：运用聚合酶链反应- 序列特异性引物（PCR-SSP ）方法分析106 例女性乳腺癌患者和116 例正常对照女性FGFR2 基因内含子5 rs 1219648 多态性的分布情况。结果：乳腺癌组FGFR2 基因单核苷酸多态性位点rs 1219648 的基因型（TT,TC,CC）频率分别为50.00% 、25.47% 和24.53% ,对照组分别为29.31% 、48.28% 和22.41% ,乳腺癌组与对照组T 等位基因频率分别为62.74% 和53.45% ,C 等位基因频率分别为37.26% 和46.55% ,FGFR2 rs 1219648 基因型频率及等位基因频率在乳腺癌组与对照组中的分布差异均有统计学意义（P<0.05）。 结论：FGFR2 基因内含子5 的单核苷酸位点rs 1219648 多态性与乳腺癌可能具有相关性。携带FGFR2 rs 1219648 的TT等位基因型的人群可能更易患乳腺癌。     

Associations between Single Nucleotide Polymorphisms of COX-2 and MMP-2 Genes and Colorectal Cancer Susceptibility in the Saudi Population

Background: It has been reported that COX-2 expression is associated with MMP-2 expression in thyroid and breast cancers, suggesting that MMPs are linked to COX-2-mediated carcinogenesis. Several polymorphisms within the MMP2 promoter region have been reported in cases with oncogenesis and tumor progression, especially in colorectal carcinogenesis. Materials and Methods: This research evaluated risk of association of the SNPs, including genes for COX-2 (A/G transition at +202) and MMP-2 (C/T transition at-1306), with colorectal cancer in 125 patients and 125 healthy controls. Results and Conclusions: Our data confirmed that MMP2 C-1306 T mutations were significantly more common in colon cancer patients than in our control Saudi population; p=0.0121. On the other hand in our study, there was no significant association between genotype distribution of the COX2 polymorphism and colorectal cancer; p=0.847. An elevated frequency of the mutated genotype inthe control group as compared to the patients subjects indeed suggested that this polymorphism could decrease risk in the Saudi population. Our study confirmed that the polymorphisms that could affect the expressions of MMP-2 and COX-2 the colon cancer patients were significantly higher than that in the COX-2 negative group. The frequency of individuals with MMP2 polymorphisms in colon cancer patients was higher than individuals with combination of COX2 and MMP2 polymorphisms. Our study confirmed that individuals who carried the polymorphisms that could affect the expressions of COX2 are more susceptible to colon cancer. MMP2 regulatory polymorphisms could be considered as protective; further studies need to confirm the results with more samples and healthy subjects.     

Association Between Single Nucleotide Polymorphisms in the XRCC1 Gene and Susceptibility to Prostate Cancer in Chinese Men

Background: Prostate cancer (Pca) is one of the most common complex and polygenic diseases in men. TheX-ray repair complementing group 1 gene (XRCC1) is an important candidate in the pathogenesis of Pca. Thepurpose of this study was to evaluate the association between single nucleotide polymorphisms in the XRCC1gene and susceptibility to Pca. Materials and Methods: XRCC1 gene polymorphisms and associations withsusceptibility to Pca were investigated in 193 prostate patients and 188 cancer-free Chinese men. Results: Thec.910A>G variant in the exon9 of XRCC1 gene could be detected by polymerase chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) and DNA sequencing methods. Significantly increased susceptibility toprostate cancer was noted in the homozygote comparison (GG versus AA: OR=2.95, 95% CI 1.46-5.42, χ2=12.36,P=0.001), heterozygote comparison (AG versus AA: OR=1.76, 95% CI 1.12-2.51, χ2=4.04, P=0.045), dominantmodel (GG/AG versus AA: OR=1.93, 95% CI 1.19-2.97, χ2=9.12, P=0.003), recessive model (GG versus AG+AA:OR=2.17, 95% CI 1.33-4.06, χ2=8.86, P=0.003) and with allele contrast (G versus A: OR=1.89, 95% CI 1.56-2.42,χ2=14.67, P<0.000). Conclusions: These findings suggest that the c.910A>G polymorphism of the XRCC1 geneis associated with susceptibility to Pca in Chinese men, the G-allele conferring higher risk.     

Meta-analysis of Associations between Interleukin-17 Gene Polymorphisms and Risk of Gastric Cancer

Background: Previous studies have indicated that single nucleotide polymorphisms (SNPs) of the interleukin-17(IL-17) gene are associated with an increased risk of gastric cancer. However, the findings were inconsistent.Materials and Methods: To provide a more reliable estimation of the association between SNPs in the IL-17gene and the susceptibility to gastric cancer, we searched PubMed, CNKI, and Wan Fang databases and selectedfinally six studies covering 2,366 cases and 3,205 controls to perform a meta-analysis. Results: Statistical analysesshowed that an rs2275913 polymorphism within the IL-17A gene was significantly associated with an increasedrisk of gastric cancer using a generalized odds ratio (ORG, a model-free approach). Moreover, we also found thatthe ‘A’ allele carriers of IL-17A rs2275913 had a significant link with clinicopathological features. However, nosignificant positive signals were observed in the association analysis of the rs3748067 and rs763780 polymorphismswith the risk of gastric cancer in IL-17A and IL-17F, respectively. Conclusions: Despite some limitations, thepresent meta-analysis provided a more precise estimation of the relationship between the IL-17 gene SNPs andgastric cancer risk compared with individual studies.     

Nucleotide Excision Repair Capacity and XPC and XPD Gene Polymorphism Modulate Colorectal Cancer Risk

Background

Colorectal cancer (CRC) is leading malignant tumors to occur mainly in industrialized countries, where it exhibits one of the highest mortality rates. Up to 80% of all CRCs characterize a chromosomal instability (CIN) phenotype. The main challenge faced by scientist is to reveal the mechanism of CIN development. An often proposed model is defects in DNA repair in terms of efficiency and genetic variations that modulate the response to stimuli from the environment. The objectives of this research were to determine whether nucleotide excision repair (NER) might affect CRC risk.

HER2Ile655Val Single Nucleotide Polymorphism Associated with Early-Onset Breast Cancer Susceptibility: A Systematic Review and Meta-Analysis

ackground: Human epidermal growth factor receptor 2 (HER2) plays an important role in the development and progression of breast cancer. To understand the precise association, this meta-analysis was conducted to estimate the association between HER2Ile655Val single nucleotide polymorphism (SNP) and susceptibility to early-onset breast cancer. Methods: A comprehensive database retrieval from PubMed, Embase, Web of Science and Google Scholar was pooled to investigate links between the HER2Ile655Val SNP and risk of breast cancer. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to appraise the association under the additive model (Ile vs. Val), dominant model (Val/Val + Ile/Val vs. Ile/Ile), and recessive model (Val/Val vs. Ile/Val + Ile/Ile). Results: Seventeen relevant studies with 11,749 cases and 8,105 controls were finally included. We found that HER2Ile655Val SNP is associated with an increased risk of breast cancer in an additive and dominant model. In the subgroup analysis with age stratification, a significant association between the HER2 codon 655 SNP and the risk of breast cancer was found in young women in an additive, dominant, and recessive model; conversely, no significant associations were indicated in older women. In the breast cancer subgroup, HER2Ile655Val SNP was significantly associated with younger age women with breast cancer in the dominant model. In contrast, no association between the HER2 codon 655 SNP and age was found in control populations. Conclusion: Our findings suggest that the Val allele in HER2 codon 655 SNP is strongly associated with breast cancer susceptibility in the young female population and is also significantly associated with younger age in women with breast cancer. HER2Ile655Val SNP might be a susceptibility factor that favours early-onset breast cancer.     

P21 Ser31Arg and FGFR2 rs2981582 Polymorphisms as Risk Factors for Early Onset of Breast Cancer in Yogyakarta,Indonesia

Objectives: Breast cancer tend to be more progressive with poorer prognosis in younger patients than those at an older age. Single Nucleotide Polymorphisms (SNPs) of P53 Pro72Arg, MDM2 SNP309, P21 Ser31Arg, ER SNP594, HER2 Ile655Val, and FGFR2 rs2981582 have drawn attention as genetic factors associated with cancer risk. However, there were contradictory results involving different races and their association is still unknown in Indonesian populations. This study was performed to examine the proportion of these six genes polymorphisms and their associations with age of onset of breast cancer patients in Yogyakarta, Indonesia. Methods: Biorepository DNA from 199 patients registered at Dr. Sardjito Hospital Yogyakarta from 2006-2013 were tested for polymorphisms using the PCR-RFLP method. Samples were taken from two age groups; early-onset (55 years). Chi-square tests with odds ratio were used for data analysis. Results: The mean age of the early-onset group was 36±4.2 years, while the late-onset group was 62±6.9 years. AA genotype and A allele of P21 and TT genotypes and T allele of FGFR2 were significantly more frequent and were associated with an increased risk of early-onset of breast cancer (95%CI: 2.54 and 1.59; 2.63 and 1.64, respectively). Conclusions: Our study indicates that the A allele of P21 and the allele T of FGFR2 may be associated with an increased risk of early-onset of breast cancer in Yogyakarta, Indonesia. Further analysis is needed to confirm the findings.     

The Relationship Between Eight GWAS‐Identified Single‐Nucleotide Polymorphisms and Primary Breast Cancer Outcomes

Background.

Several single-nucleotide polymorphisms (SNPs) associated with breast cancer risk have been identified through genome-wide association studies (GWAS). We investigated whether eight risk SNPs identified in GWAS were associated with breast cancer disease-free survival (DFS) and overall survival (OS) rates.

Patients and Methods.

A cohort of 739 white women with early-stage breast cancer was genotyped for eight GWAS-identified SNPs (rs2981582, rs1219648 [FGFR2], rs3803662, rs12443621, rs8051542 [TOX3], rs999737 [RAD51L1], rs6504950 [17q23], and rs4973768 [3p24]). Relationships between SNPs and breast cancer outcomes were evaluated using Cox proportional hazard regression models. The cumulative effects of SNPs on breast cancer outcomes were assessed by computing the number of at-risk genotypes.

Results.

At a median follow-up of 121 months (range: 188–231 months) for survivors, 237 deaths (32%) and 186 breast cancer events (25%) were identified among the 739 patients. After adjusting for age, clinical stage, and treatment, rs12443621 (16q12; p = .03) and rs6504950 (17q23; p = .008) were prognostic for OS but not DFS. A higher risk for death was also found in the multivariable analysis of patients harboring three or four at-risk genotypes of the GWAS SNPs compared to patients carrying two or less at-risk genotypes (hazard ratio: 1.60, 95% confidence interval: 1.23–2.24; p = .0008).

Conclusion.

The study results suggest that previously identified breast cancer risk susceptibility loci, rs12443621 (16q12) and rs6504950 (17q23), may influence breast cancer prognosis or comorbid conditions associated with overall survival. The precise molecular mechanisms through which these risk SNPs, as well as others that were not included in the analysis, influence clinical outcomes remain to be determined.     

Impact of ESR1 Polymorphisms on Risk of Breast Cancer in the Chinese Han Population

BackgroundThe estrogen receptor-1 (ESR1) gene encodes estrogen receptor-α, which is a major biomarker in the development of breast cancer. This study aimed to investigate the effect of ESR1 polymorphisms on breast cancer in Chinese Han women.Materials and MethodsWe genotyped 4 candidate single nucleotide polymorphisms (SNPs) in ESR1 among 503 patients with breast cancer and 503 healthy people using the Agena MassARRAY platform. The association between ESR1 polymorphisms and breast cancer risk was evaluated using odds ratios (ORs) and 95% confidence intervals (95% CIs) under 4 genetic models. The HaploReg v4.1 and GEPIA database were used for SNP functional annotation and ESR1 expression analysis, respectively.ResultsThe T allele of rs9383938 in ESR1 was significantly associated with an increased breast cancer risk (OR, 1.26; 95% CI, 1.05-1.50; P = .013). In genetic models, rs9383938 increased breast cancer risk in the codominant model (OR, 1.54; 95% CI, 1.07-2.22; P = .021), the dominant model (OR, 1.31; 95% CI, 1.01-1.68; P = .040), and the additive model (OR, 1.24; 95% CI, 1.04-1.48; P = .017). Stratification analysis showed that rs9383938 and rs2228480 raised the breast cancer susceptibility in individuals aged younger than 52 years old. Rs1801132 of ESR1 was significantly associated with the status of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 in the allele model and genetic models (P < .05).ConclusionsThis study demonstrated that ESR1 polymorphisms might influence breast cancer susceptibility in the Chinese Han population. Further mechanism studies are needed to confirm the contribution of ESR1.