端粒维持基因多态性与膀胱癌易感性的关系(英文)

Telomere maintenance genes play an important role in maintaining the integrity of the telomere structure that protects chromosome ends,and telomere dysfunction may lead to tumorigenesis.Genetic variation in telomere maintenance genes has been confirmed.Cumulative evidence shows that the difference of telomere length and stability among the individual depends on the genetic variants of telomere maintenance genes.Genetic variants in telomere maintenance genes may affect telomere length and stability,thus the increased cancer risk.This review intends to summarize the association of genetic variants in telomere maintenance genes with bladder cancer risk.     

Genetic variants in RUNX3 and risk of bladder cancer: a haplotype-based analysis

Transforming growth factor-beta (TGF-beta) is a multifunctional growth factor that plays important roles in many biological processes, whereas RUNX3 is a target of TGF-beta-mediated tumor suppressor pathway. In humans, RUNX3 inactivation may lead to the cancer development, including bladder cancer. To determine whether the RUNX3 polymorphisms are associated with risk of bladder cancer, we conducted a case-control study of 368 bladder cancer patients and 368 cancer-free controls to assess the associations between the RUNX3 tagging single-nucleotide polymorphisms (tSNPs) and bladder cancer risk. In the single-locus analysis, we found a significantly increased risk of bladder cancer associated with the SNP7 rs760805 AA genotype (adjusted odds ratio = 1.97, 95% confidence interval = 1.44-2.69), compared with the AT/TT genotype. Haplotype-based association analysis revealed that the increased risk of bladder cancer was significantly associated with two haplotypes TATCCCAAAA (2.37, 1.16-4.83) and AGCTTGAGAG (2.70, 1.08-6.72) that included the rs760805 A allele. Multifactor dimensionality reduction (MDR) analysis identified a significant more than multiplicative interaction between the SNP7 rs760805 AA and smoking and an additive interaction between the SNP3 rs11249206 TT and smoking on bladder cancer risk. The SNP3 rs11249206, SNP5 rs1395621, SNP7 rs760805, SNP8 rs2236852 and the trichotomized cumulative smoking were the five factors best predicted by the MDR models. When the variables were combined and dichotomized and fitted into the MDR model, the subjects carrying the combined risk stratum had a significantly increased risk for bladder cancer (6.37, 4.57-8.87, P = 7.03 x 10(-28)). These results suggested that the genetic variants in RUNX3 may modulate the risk of bladder cancer.     

Genetic variants in epigenetic genes and breast cancer risk

Epigenetic events, resulting changes in gene expression capacity, are important in tumour progression, and variation in genes involved in epigenetic mechanisms might therefore be important in cancer susceptibility. To evaluate this hypothesis, we examined common variants in 12 genes coding for DNA methyltransferases (DNMT), histone acetyltransferases, histone deacetyltransferases, histone methyltrasferases and methyl-CpG binding domain proteins, for association with breast cancer in a large case-control study (N cases = 4474 and N controls = 4580). We identified 63 single nucleotide polymorphisms (SNPs) that efficiently tag all the known common variants in these genes, and are also expected to tag any unknown SNP in each gene. We found some evidence for association for six SNPs: DNMT3b-c31721t [P (2 df) = 0.007], PRDM2-c99243 t [P (2 df) = 0.03] and t105413c [P-recessive = 0.05], EHMT1-g-9441a [P (2df) = 0.05] and g41451t (P-trend = 0.04), and EHMT2-S237S [P (2df) = 0.04]. The most significant result was for DNMT3b-c31721t (P-trend = 0.124 after adjusting for multiple testing). However, there were three other results with P < 0.05. The permutation-based probability of this occurring by chance was 0.335. These significant SNPs were genotyped in 75 human cancer cell lines from different tumour types to assess if there was an association between them and six epigenetic measures. No statistically significant association was found. However, a trend was observed: homozygotes for the rare alleles of the EHMT1, EHMT2 and PRDM2 had a mean value for both trimethylation of K9 and K27 of histone H3 remarkably different to the homozygotes for the common alleles. Thus, these preliminary observations suggest the possible existence of a functional consequence of harbouring these genetic variants in histone methyltransferases, and warrant the design of larger epidemiological and biochemical studies to establish the true meaning of these findings.     

中国汉族人群前列腺癌易感性与TLR4基因单核苷酸多态性的研究

目的 探讨Asp299Gly(rs4986790)、Thr399Ile(rs4986791)、rs11536889单核苷酸多态性(SNP)与前列腺癌(PCa)易感性和严重程度的关系.方法 采用病例对照研究方法,选取组织学证据确诊的PCa患者96例为PCa组,良性前列腺增生(BPH)患者87例为BPH组,健康者92例为健康对照组.记录研究对象的临床资料并计算Gleason评分,PCR-RFLP法分析各组的基因型.结果 PCa组、BPH组及健康对照组的年龄、前列腺癌家族史所占比例、前列腺特异抗原(PSA)水平比较,差异均有统计学意义(P=0.000);PCa组、BPH组及健康对照组的Asp299Gly和Thr399Ile基因型频率分布比较,差异无统计学意义(P﹥0.05),但3组间rs11536889基因型频率分布比较,差异有统计学意义[PCa组/(BPH组+健康对照组),CC/GC vs GG,OR=2.152,95%CI:1.280~3.618,P﹤0.05];Gleason评分≥7分组GC+CC分布比例高于Gleason评分﹤7分组(OR=2.378,95%CI:1.042~4.427,P﹤0.05).结论 TLR4基因rs11536889 SNP可能与PCa发病和病情严重程度相关.     

Association between glutathione S-transferase M1 null variant and risk of bladder cancer in Chinese Han population

Glutathione S-transferase M1 (GSTM1) is one of the most important families of phase II isoenzymes known to detoxify a variety of electrophilic compounds and carcinogens. The GSTM1 null variant is associated with decreased enzyme activity, and it has been assumed to be associated with bladder cancer. The association between the GSTM1 null variant and bladder cancer in the Chinese Han population was unclear owing to the obvious inconsistency from published studies. To quantify the association between the GSTM1 null variant and bladder cancer in the Chinese Han population, we carried out the meta-analysis. We estimated the pooled odds ratio (OR) with its 95 % confidence interval (95 % CI) to assess the association. Eight studies with a total of 3,887 individuals were finally included into the meta-analysis. Overall, there was an obvious association between the GSTM1 null variant and risk of bladder cancer in the Chinese Han population (OR?=?1.61, 95 % CI 1.41–1.84, P?<?0.001). There was no heterogeneity across those eight studies (I ²?=?0 %). The cumulative meta-analyses showed a trend of more obvious association between the GSTM1 null variant and risk of bladder cancer in the Chinese Han population as data accumulated by year. There was no obvious evidence of publication bias in the meta-analysis. In conclusion, the GSTM1 null variant is significantly associated with risk of bladder cancer in the Chinese Han population.     

Evaluation of genetic variants in microRNA-related genes and risk of bladder cancer

MicroRNAs (miRNA) are small noncoding RNA molecules involved in a diversity of cellular functions. Although it has been reported that global suppression of the miRNA biogenesis pathway leads to enhanced tumorigenesis, the effect of common genetic variants of miRNA-related genes on cancer predisposition is unclear. To better understand this effect, we genotyped 41 single-nucleotide polymorphisms (SNP) from 24 miRNA-related genes in a case-control study conducted in 746 Caucasian patients with bladder cancer and 746 matched controls. The homozygous variant genotype of a nonsynonymous SNP in the GEMIN3 gene (rs197414) was associated with a significantly increased bladder cancer risk [odds ratios (OR), 2.40; 95% confidence interval (95% CI), 1.04-5.56]. Several additional miRNA-related SNPs were also identified that showed a borderline significant association with bladder cancer risk. Haplotype analysis indicated that a common haplotype of the GEMIN4 gene was associated with a significantly increased bladder cancer risk with an OR of 1.25 (95% CI, 1.01-1.54). To assess the aggregate effects of the promising SNPs, we performed a combined unfavorable genotype analysis that included all SNPs showing at least a borderline statistical significance. We found that, compared with the low-risk reference group with less than two unfavorable genotypes, the medium-risk group with two unfavorable genotypes exhibited a 1.29-fold (0.92-1.81) increased risk whereas the high-risk group with more than two unfavorable genotypes exhibited a 1.92-fold (1.36-2.71) increased risk (P(trend) < 0.0001). Overall, this is the first epidemiologic study showing that miRNA-related genetic variants may affect bladder cancer risk individually and jointly.     

Genetic variants in cell cycle control pathway confer susceptibility to bladder cancer

BACKGROUND

Cell cycle checkpoint regulation is crucial for the prevention of carcinogenesis in mammalian cells.

METHODS

To test the hypothesis that common sequence variants in the cell cycle control pathway may affect bladder cancer susceptibility, the effects of a panel of 10 potential functional single nucleotide polymorphisms (SNPs) from 7 cell cycle control genes, P53, P21, P27, CDK4, CDK6, CCND1, and STK15, were evaluated on bladder cancer risk in a case‐control study of 696 bladder cancer cases and 629 healthy controls.

RESULTS

Overall, on individual SNP analysis only individuals with the p53 intron 3 16‐bp duplication polymorphism variant allele had a significantly reduced bladder cancer risk (odds ratio [OR] = 0.74, 95% confidence interval [CI], 0.56–0.96). This effect was more evident in former smokers and younger subjects. We then applied the Classification and Regression Tree (CART) statistical approach to explore the high‐order gene‐gene and gene‐smoking interactions. In the CART analysis, smoking status was identified as the most influential factor for bladder cancer susceptibility. The final decision tree by CART contained 6 terminal nodes. Compared with the second‐lowest risk group the ORs for terminal nodes 1 and 3 to 6 ranged from 0.46 to 6.30.

CONCLUSIONS

These results suggest that cell cycle genetic polymorphisms may affect bladder cancer predisposition through modulation of host genome stability and confirm the importance of studying gene‐gene and gene‐environment interactions in bladder cancer risk assessment. Cancer 2008. © 2008 American Cancer Society.     

Genetic variants of NBS1 predict clinical outcome of platinum-based chemotherapy in advanced non-small cell lung cancer in Chinese

Objective: NBS1 plays a key role in the repair of DNA double-strand break (DSB). We conducted this study to investigate the effect of two critical polymorphisms (rs1805794 and rs13312840) in NBS1 on treatment response and prognosis of advanced non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy. Methods: Using TaqMan methods, we genotyped the two polymorphisms in 147 NSCLC patients. Odds ratios (ORs) and their 95% confidential intervals (CIs) were calculated as a measure of difference in the response rate of platinum-based chemotherapy using logistic regression analysis. The Kaplan-Meier and log-rank tests were used to assess the differences in progression-free survival (PFS) and overall survival (OS). Cox proportional hazards model was applied to assess the hazard ratios (HRs) for PFS and OS. Results: Neither of the two polymorphisms was significantly associated with treatment response of platinum-based chemotherapy. However, patients carrying the rs1805794 CC variant genotype had a significantly improved PFS compared to those with GG genotype (16.0 vs. 8.0 months, P = 0.040). Multivariable cox regression analysis further showed that rs1805974 was a significantly favorable prognostic factor for PFS [CC/CG vs. GG: Adjusted HR = 0.62, 95% CI: 0.39-0.99; CC vs. CG/GG: Adjusted HR = 0.56, 95% CI: 0.32-0.97). Similarly, rs13312840 with a small sample size also showed a significant association with PFS (CC vs. CT/TT: Adjusted HR = 25.62, 95% CI: 1.53-428.39). Conclusions: Our findings suggest that NBS1 polymorphisms may be genetic biomarkers for NSCLC prognosis especially PFS with platinum-based chemotherapy in the Chinese population.     

Genetic variants of myeloperoxidase and catechol-O-methyltransferase and breast cancer risk.

This nested case-control study evaluated the role of polymorphisms in the myeloperoxidase (MPO) and catechol-O-methyltransferase (COMT) genes that modulate oxidative stress in breast cancer risk in a Chinese population. Our results demonstrate that the MPO A/A genotype was associated with a reduced risk of breast cancer (odds ratio (OR) 0.64; 95% confidence interval (CI) 0.11-3.76), whereas there was no overall association of COMT genotype with breast cancer. Of note, an elevated breast cancer risk associated with the increasing numbers of high-risk genotypes of MPO and COMT genes was observed in women with a longer duration between menarche and first full-term pregnancy.     

Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk

Individual susceptibility to the toxic effects of cigarette smoke may be modified by inherited variability in carcinogen metabolism. The purpose of the present study was to investigate pancreatic cancer risk associated with cigarette smoking and 33 variants within carcinogen metabolism genes and examine whether these variants modify the association between smoking and pancreatic cancer. A population-based study was conducted with 455 pancreatic cancer cases and 893 controls. Epidemiological and smoking data were collected from questionnaires and variants were genotyped by mass spectrometry. Age- and sex-adjusted odds ratio (ASOR) and multivariate-adjusted odds ratio (MVOR) estimates were obtained using multivariate logistic regression, and interactions between each variant and smoking were investigated. Current smoker status [MVOR = 2.29, 95% confidence interval (95% CI): 1.62, 3.22], 10-27 pack-years (MVOR = 1.57, 95% CI: 1.13, 2.18), >27 pack-years (MVOR = 1.77, 95% CI: 1.27, 2.46) and longer durations of smoking (19-32 years: MVOR = 1.46, 95% CI: 1.05, 2.05; >32 years: MVOR = 1.78, 95% CI: 1.30, 2.45) were associated with increased pancreatic cancer risk. CYP1B1-4390-GG (ASOR = 0.36, 95% CI: 0.15, 0.86) and Uridine 5'-diphospho glucuronosyltransferase 1 family, polypeptide A7-622-CT (ASOR = 0.77, 95% CI: 0.60, 0.99) were associated with reduced risk. N-acetyltransferase 1-640-GT/GG (ASOR = 1.75, 95% CI: 1.00, 3.05), GSTM1 (rs737497)-GG (ASOR = 1.41, 95% CI: 1.02, 1.95), GSTM1 gene deletion (ASOR = 4.89, 95% CI: 3.52, 6.79) and glutathione S-transferase theta-1 gene deletion (ASOR = 4.41, 95% CI: 2.67, 7.29) were associated with increased risk. Significant interactions were observed between pack-years and EPHX1-415 (P = 0.04) and smoking status and N-acetyltransferase 2-857 (P = 0.03). Variants of carcinogen metabolism genes are independently associated with pancreatic cancer risk and may modify the risk posed by smoking.     

Fluid intake,genetic variants of UDP-glucuronosyltransferases,and bladder cancer risk

Background:

Results of studies of fluid consumption and its association with bladder cancer have been inconsistent. Few studies have considered modification effects from genetic variants that may interact with the type of consumed fluids. UDP-glucuronosyltransferases (UGTs), which are membrane-bound conjugating enzymes, catalyse the transformation of hydrophobic substrates to more water-soluble glucuronides to facilitate renal or biliary excretion. Whether genetic variants in UGTs could modulate the association between fluid intake and bladder cancer has not been studied.

Methods:

We conducted a case–control study with 1007 patients with histopathologically confirmed bladder cancer and 1299 healthy matched controls. Fluid intake and epidemiologic data were collected via in-person interview. Multivariate unconditional logistic regression was used to estimate odds ratios (ORs) and the 95% confidence intervals (95% CI).

Results:

After adjustment for potential confounders, high quantity of total fluid intake (⩾2789 vs <1696 ml per day) conferred a 41% increased risk of bladder cancer (OR=1.41; 95% CI=1.10–1.81). Specific fluids such as regular soft drinks and decaffeinated coffee were also associated with increased risks, whereas tea, wine, and liquor were associated with decreased risks. Among 83 single-nucleotide polymorphisms in the UGT gene family, 18 were significantly associated with bladder cancer risk. The most significant one was rs7571337, with the variant genotype conferring a 29% reduction in risk (OR=0.71; 95% CI=0.56–0.90).

Conclusions:

Total and specific fluid intakes are associated with bladder cancer risk in the study population and that genetic variants of UGT genes could modulate the effects. These results facilitate identification of high-risk individuals and have important implications in bladder cancer prevention.     

Genetic alterations in bronchial mucosa and plasma DNA from individuals at high risk of lung cancer

Evidence suggests that the majority of lung cancer patients have tumour-derived genetic alterations in circulating plasma DNA, and that this may be developed as a diagnostic tool. To this end, we have studied 60 individuals attending bronchoscopy clinic, with symptoms suspicious of lung cancer, for genetic alterations in bronchial mucosa biopsy (n = 47) and plasma (n = 40) DNA. Thirteen of 47 individuals from whom biopsies were taken displayed allelic loss of heterozygosity (LOH) in biopsy DNA for at least 1 of 4 markers. All 13 of these individuals had neoplastic tumour cells in their biopsies and were subsequently diagnosed with cancer. Thirteen of 40 individuals from whom plasma was taken displayed a plasma DNA LOH, and 12 of these 13 individuals were subsequently diagnosed with cancer. LOH in plasma was generally representative of LOH in the corresponding biopsy. In terms of sensitivity, using just 4 markers, biopsy LOH and plasma LOH were found in 13 of 44 (30%) and 12 of 29 (41%), respectively, of those patients subsequently diagnosed with cancer. Two patients were positive for LOH in plasma samples that pre-dated a diagnosis of cancer by several months. These data suggest that assay of genetic alterations in circulating plasma DNA may be developed as a useful addition to conventional techniques for the diagnosis of lung cancer.     

膀胱癌预后免疫相关风险模型的构建分析

目的:通过构建免疫相关风险模型用于评估膀胱癌(bladder cancer,BC)预后,探讨免疫相关基因(immune-related genes,IRGs)在BC临床应用价值.方法:基于TCGA、ImmPort、Cistrom等数据库分别下载BC转录组测序数据(RNA-seq)、IRGs和转录因子(transcrip...     

膀胱癌miRNAs风险预后模型建立与应用

目的:通过筛选与膀胱癌生存预后相关的非编码小分子核糖核酸(microRNAs,miRNAs),构建风险预后模型评价患者预后.方法:从人类癌症基因图谱(The Cancer Genome Atlas,TCGA)数据库下载膀胱癌miRNAs与mRNAs数据及对应的临床相关信息,筛选差异的miRNAs和mRNAs.对差异的m...     

Breast cancer surface receptors predict risk for developing brain metastasis and subsequent prognosis

Determining the status of breast cancer surface receptors (estrogen receptor, progesterone receptor, HER2/neu) has become routine in the care of patients with this disease and has proven to be helpful in guiding treatment. For this reason, breast cancer has become a model for molecularly guided therapy in solid tumors. Emerging data support that these receptors are associated with risk for developing brain metastases. Additionally, once brain metastases have occurred these receptors may also correlate with prognosis.