Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer.

BACKGROUND: Gastric cancer is the second highest cause of cancer mortality in the world, despite declining rates of incidence in many industrialized countries. We carried out a case-control study to evaluate whether polymorphisms of DNA repair and glutathione S-transferase (GST) genes modulate the risk of developing diffuse gastric cancer. METHODS: ERCC1 118 T/C, XRCC1 399 G/A, XPD 312 G/A, XPD 751 A/C, XRCC3 241 C/T, MS 919 A/G, GSTP1 105 A/G, GSTM1-null/positive and GSTT1-null/positive genotypes were obtained for a series of 126 Helicobacter pylori-negative diffuse gastric cancer patients and 144 Helicobacter pylori-negative controls sampled from the population of Marche, an area with high gastric cancer risk in central Italy. RESULTS: GSTP1 105 A/G and GSTP1 105 G/G genotypes were identified as protective factors, with odds ratio (OR) of 0.4 (95% CI 0.17-0.81, p=0.01) and OR=0.58 (95% CI 0.33-1, p=0.05), respectively. GSTT1-null genotype was identified as a protective factor, with OR=0.48 (95% CI 0.22-0.99, p=0.04). There was no significant difference between cases and controls for XPD 751 A/C, ERCC1 118 T/C, XRCC3 241 C/T, XRCC1 399 G/A, XPD 312 G/A, GSTM1-null/positive and MS 919 A/G polymorphisms. CONCLUSIONS: This study suggests that GSTP1 105A/G and GSTT1-null/positive genotypes might be associated with a reduced risk for sporadic diffuse gastric cancer. Clin Chem Lab Med 2007;45:822-8.     

ERCC1 and XPD/ERCC2 Polymorphisms’ Predictive Value of Oxaliplatin‐Based Chemotherapies in Advanced Colorectal Cancer has an Ethnic Discrepancy: A Meta‐analysis

Our purpose is to evaluate the predictive value of the genetic polymorphisms of Excision repair cross‐complementing group 1 (ERCC1) and xeroderma pigmentosum group D/excision repair cross‐complementing group 2 (XPD/ERCC2) in patients with advanced colorectal cancer receiving oxaliplatin‐based chemotherapy, and we performed a meta‐analysis in order to obtain a more precise estimation for a more optimizing individual chemotherapy. The relevant cohort studies were identified by searching the electronic databases of MEDLINE, EMBASE, and CNKI. We used ‘‘colorectal,’’ ‘‘cancer,’’ ‘‘carcinoma,’’ ‘‘ERCC1,’’ ‘‘XPD or ERCC2,’’ ‘‘polymorphism,’’ ‘‘oxaliplatin,’’ ‘‘treatment,’’ or ‘‘chemotherapy’’ as key words. Inclusion criteria were patients with advanced colorectal cancer receiving oxaliplatin‐based chemotherapy, evaluation of polymorphism of ERCC1 and XPD/ ERCC2, and overall response rate (ORR). In this meta‐analysis, a total of seven studies were selected according to the inclusion criteria. Five studies investigated ERCC1 codon 118 polymorphisms and three studies evaluated XPD/ERCC2 codon 751 polymorphisms. For ERCC1 codon C118T polymorphism, the ORR to oxaliplatin‐based chemotherapy in patients with C/C wild genotype was 77.27% and it was 69.30% for C/T and T/T variant genotype. The pooled odds ratio (OR) for C/C wild‐type vs. C/T and T/T genotype was 1.11 (95% CI, 0.86–1.42; P = 0.42). For XPD/ERCC2 Lys751Gln polymorphism, the response rate was 86.58 and 67.57% in patients with the A/A and either one or two C alleles (A/C or C/C) respectively, and the pooled OR was 1.15 (95% CI, 1.01–1.30; P = 0.03). Furthermore, we chose subgroup analysis in order to find the difference between the Caucasian and Asian ethnicity. The results indicated that Oxaliplatin sensitivity was significantly associated with ERCC1 C118T polymorphism in Asian people. XPD/ERCC2 Lys751Gln polymorphism had the predictive value especially for the patients from the America and Europe.     

DNA修复基因多态性与胃癌易感性的关系

目的分析中国西南地区人群DNA修复基因XRCCl和XPD基因多态性分布,探讨XRCCl和XPD基因多态性与胃癌发病风险的关系。方法采用1：1病例对照研究方法,采用基因测序法检测160例胃癌患者及160例正常人外周血GSTPl基因XPDAsp312Asn,XRCClArgl94Trp,和XRCClArg280His多态性,进行胃癌风险分析。结果胃癌组与正常对照组相比,XPD312、XRCCl280位点的多态性分布频率无明显差异,而XRCCl194Trp的分布频率在病例组和对照组中分别为17．2％和7．3％,具有统计学差异。XRCCl194Trp等位基因的个体其胃癌风险增高（OR=2．72,95％CI=1．04~7．24,P=0．027）。结论XRCClArgl94Trp基因多态性可增加人群患胃癌的风险,XPDAsp312Asn、XRCClArg280His基因多态性与胃癌易感性无关联。     

XRCC1 polymorphism and lung cancer risk

DNA repair plays a critical role in protecting the genome of the cell from the insults of carcinogens or ionizing radiation. Reduced DNA repair capacity can increase the susceptibility to environmental- or occupational-induced cancers. Three coding polymorphisms at codon 194, codon 280 and codon 399 in the x-ray cross complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. In this review, we summarize the literature and discuss the relevance of XRCC1 polymorphisms and lung cancer risk. The frequency of genetic polymorphisms is dependent on the ethnic origins of a population. The frequency of the variant allele of codon 194 among Asians is on average 31.2% (95% confidence interval [CI]: 29.6-32.8), which is significantly higher than among Caucasians (6.6%; 95% CI: 5.9-7.4) or Africans (7.3%; 95% CI: 5.7-9.2). The variant allele in codon 399 occurs among Africans at a frequency of 15.5% (95% CI: 13.5-17.7), 34.7% in Caucasians (95% CI: 33.8-35.6) and 26.5% in Asians (95% CI: 25.6-27.4). Results regarding lung cancer risk are inconsistent. The lung cancer risk associated with polymorphisms of the XRCC1 codon 194 demonstrate an odds ratio (OR) of around 1.0. For the XRCC1 codon 280, lung cancer risk varied between ORs of 0.26 and 1.8; and for the XRCC1 codon 399 between 0.32 and 3.25. Only two studies showed significantly elevated risks (OR: 3.25; 95% CI: 1.2-10.7; OR: 1.3; 95% CI: 1.0-1.8, respectively), whereas one study showed a decreased lung cancer risk (OR: 0.60; 95% CI: 0.46-40.80). Lung cancer risk increased with cigarette smoking. A significant association was not observed between the single-nucleotide polymorphisms and tobacco-related cancers. Lung cancer risk increased significantly for the variant XRCC1 -77 genotypes (TC and CC) compared with the TT genotype (OR: 1.46; 95% CI: 1.18-1.82). The risk was more pronounced in smokers (OR: 1.63; 95% CI: 1.20-2.21) than in nonsmokers (OR: 1.28; 95% CI: 0.94-1.76). No association with polymorphisms were found for various histological tumor types. The XRCC1 399 Gln/Gln variant genotype was associated with a higher median survival time.     

XRCC1、XPD单核苷酸多态性与肺癌铂类化疗的临床预后研究

目的DNA修复基因XRCC1和XPD是参与铂-DNA加合物修复中的关键因子。探讨肿瘤石蜡组织中XR- CC1、XPD单核苷酸多态性与接受铂类药物化疗非小细胞肺癌(NSCLC)患者临床预后之间的关系。方法采用TaqMan探针Real-time PER方法评价53例石蜡包埋NSCLC组织中DNA修复基因XRCC1第399位密码子、XPD第751位密码子的多态性,并比较不同基因型与NSCLC肿瘤组织临床病理及铂类化疗预后之间的关系。结果XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC患者临床及肿瘤病理特征均未见相关性。携带XRCC1 Arg/Arg或Arg/Gln基因型NSCLC患者经铂类化疗后的平均总生存时间为24.0月,而携带Gln/Gln基因型患者仅为8.0月,两者有统计学差异(P=0.02)。XPD Lys751Gln与NSCLC患者无进展生存期和总生存时间均未见显著性差异(P>0.05)。XPD和XRCC1的多态性联合分析显示变异型等位基因的个数增加与总生存时间(P=0.015)相关。Cox比例风险模型显示XRCC1 Arg399Gln可以独立预测NSCLC患者的总生存时间(P=0.011)。结论XRCC1 Arg399Gln、XPD Lys751Gln基因多态性与NSCLC肿瘤临床病理特征无关。XRCC1 Arg399Gln基因多态性与NSCLC患者的总生存时间有关,在一定程度上可以作为判断NSCLC患者铂类药物化疗的预后指标。XRCC1和XPD SNP在铂类药物化疗预后方面可能存在一定的联合作用。     

Use of pyrosequencing to detect clinically relevant polymorphisms of genes in basal cell carcinoma

BACKGROUND: Pyrosequencing is a new method to detect single nucleotide polymorphisms (SNPs). Basal cell carcinoma (BCC) is one of the most common neoplasms in the world, and its incidence has been increasing worldwide in recent years. BCC is caused by an interplay between genetic and environment factors. METHODS: Pyrosequencing and restrict fragment length polymorphism (RFLP) were used in the study. We conducted a case-control association study in BCC cases and controls from Sweden. For SNPs in IL-6, IL-10 and IL-1beta, 241 cases were at the age of 27-70 years (mean 50 years) and 260 healthy controls were 26-71 years (mean 48 years), 241 cases were 27-70 years (mean 50 years) and 574 healthy controls were 22-74 years (mean 52 years) for cyclin D1 G870A, 197 cases were 29-69 years (mean 47 years) and 574 healthy controls were 22-74 years (mean 52 years) for MTHFR C677T and A1298C. Nine SNPs for IL-6-174G/C, -634G/C and -597G/A; IL-10-1082G/A and -592C/A; IL-1beta-511C/T; cyclin D1 G870A; MTHFR C677T and A1298C were analyzed. RESULTS: Most genotype distributions were in accordance with Hardy-Weinberg equilibrium (HWE), except IL-10-1082G/A, which had a significantly deviation from HWE in BCC cases (P<0.05). Linkage disequilibrium was observed between the -174 and -597 alleles in the IL-6 gene in the studied populations. The differences for cyclin D1 G870A and methylenetetrahydrofolate reductase (MTHFR) C677T were found between BCC cases group and control group (P<0.05, OR=1.34, 95% CI, 1.00-1.74; P<0.05, OR=1.67, 95% CI, 1.13-2.47, respectively). CONCLUSIONS: Cyclin D1 G870A and MTHFR C677T were associated with BC cases from Sweden, the other SNPs studied here were not associated with BCC, but chance cannot be excluded.     

XRCC3基因Thr241Met(rs861539)位点单核苷酸多态性与鼻咽癌的相关性

目的:研究XRCC3基因Thr241Met (C/T,rs861539)位点多态性与广东鼻咽癌的相关性.方法:应用PCR方法对127例广州鼻咽癌患者和117例健康对照人群的DNA标本rs861539位点进行扩增、纯化及测序,再结合人群临床资料进行统计学分析.结果:rs861539 C＞T,其中杂合型C/T基因型频率在对照组中分布较高(OR=0.473,95％ CI=0.244～ 0.917,P＜0.05);经年龄及性别分层分析,杂合子在年龄≤30岁(OR＝0.071,95％ CI=0.007～0.722,P＜0.05)以及男性(OR=0.469,95％ CI=0.232～0.947,P＜0.05)人群中在对照组分布较高;而在年龄＞ 30岁以及女性人群中两组间分布均无统计学差异.纯和突变型T/T基因型在两组间分布差异无显著性(OR=1e9,95％ CI=0～∞,P＞0.05),经年龄及性别分层分析,在两组间仍无统计学差异.结论:XRCC3基因Thr241Met (C/T,rs861539)基因多态性可能与鼻咽癌易感性无显著相关性.     

胃癌病人ERCC1和XPD基因多态性与奥沙利铂化疗预后关系

目的了解DNA损伤修复基因ERCC1 Asn118Asn和XPD Lys751Gln多态性与接受以奥沙利铂为基础化疗的晚期胃癌病人预后的关系。方法 90例晚期胃癌病人接受奥沙利铂化疗前抽取静脉血并提取DNA,应用real-ti me PCR法进行基因分型。比较病人不同基因型与生存期的关系。结果晚期胃癌病人ERCC1Asn118Asn基因型频率为C/C 47.78%,C/T42.22%,T/T10.00%;XPD基因型频率分别为A/A80.00%,A/C16.67%,C/C 3.33%。90例胃癌病人中位无疾病进展生存期（TTP）6.4个月,总生存期（OS）9.5个月。ERCC1C/C基因型病人中位TTP为6.6个月,OS为9.7个月;C/T＋T/T型病人中位TTP为6.1个月,OS为9.1个月,二者差异无统计学意义（P〉0.05）。XPD A/A基因型病人中位TTP为6.7个月,OS为9.7个月;A/C＋C/C基因型病人中位TTP为4.8个月,OS为7.8个月,二者差异有统计学意义（χ2=20.244、17.113,P〈0.05）。同时携带ERCC1 C/C及XPD A/A基因型、ERCC1 C/C及XPD A/C＋C/C基因型、ERCC1 C/T＋T/T及XPD A/A基因型、ERCC1 C/T＋T/T及XPD A/C＋C/C基因型的病人中位TTP分别为6.9、4.7、6.3和5.0个月,OS为9.9、7.7、9.3、8.0个月,4组差异有统计学意义（χ2=18.331、12.742,P〈0.05）。结论 XPD Lys751Gln基因多态性与以接受奥沙利铂为基础化疗的晚期胃癌病人的生存期有关,ERCC1 Asn118Asn基因多态性与接受奥沙利铂为基础化疗的晚期胃癌病人的生存期无关。     

XRCC1和XPD基因多态性与喉癌遗传易感性的关系

目的:探讨X线修复交叉互补组1基因(X-ray repair cross complementing group 1,XRCC1)、人类着色性干皮病基因D(xeroderma pigmentosum complementary group D,XPD)多态性与喉癌遗传易感性的关系。方法:采用病例-对照设计方法对72例经病理确诊的喉鳞状细胞癌患者(病理组)和随机抽取的72例非癌症患者为对照组,均进行一般资料问卷调查和抽取外周静脉血进行XRCC1-Arg399Gln、XPD-Lys751Gln多态性检测和聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)检测。结果:与携带XRCC1-399野生型(Arg/Arg)个体相比,病例组XRCC1第399位密码子杂合型(Arg/Gln)及突变型(Gln/Gln)分布频率高于对照组(P0.05),携带该基因型的个体喉癌的发病风险升高3.37(OR=3.37,95%,CI=1.69-6.70)倍;XPD-Lys751Gln各基因型差异2组间无统计学意义;交互作用分析显示,吸烟与不吸烟患者比较,携带XRCC1-399Arg/Gln+Gln/Gln基因型个体的喉癌发病风险差异未发现有统计学意义(χH2=0.09)。结论:XRCC1-399位点Arg→Gln的氨基酸替换可能导致喉癌的发病风险增加,XRCC1-Arg399Gln多态性可能与喉癌的遗传易感性有关。     

The methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and cancer risk: the Croatian case-control study

OBJECTIVES: Methylation abnormalities appear to be important for the pathogenesis of many cancer types. Since methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the methylation process catalyzing reduction of 5,10-methylenetetrahydrofolate to 5-methyl-tetrahydrofolate, C677T polymorphism, which decreases enzyme activity, may be associated with cancer susceptibility. The aim of this work was to investigate the distribution of MTHFR C677T polymorphism between various types of cancer and cancer-free controls and to assess if there is a difference in frequency. MATERIALS AND METHODS: 269 Cancer cases (95 prostate cancer, PC; 81 head and neck, HN; and 93 breast cancers, BC) and 102 healthy controls, free of cancer, were genotyped for C677T MTHFR polymorphism using the PCR-RFLP method. RESULTS: There was no overall difference in C677T genotype distribution between total cancer cohort and controls (p=0.064). However, a significant difference and protective OR was found for the C/T genotype (OR=0.574, 95% CI=0.352-0.935). In a comparison of different cancer types and respective controls, genotype frequencies were significantly different between head and neck carcinoma and controls (p=0.004), again with protective role of C/T genotype (OR=0.356, 95% CI=0.189-0.671). Moderate overrepresentation of C/T was found in respective male controls when compared with prostate cancer patients (p value was 0.074 for C/T vs. C/C comparison). The OR for heterozygous C/T genotype in prostate cancer group was 0.404, pointing to its putative protective role. Genotype and allelic frequencies did not differ significantly between 93 breast cancer patients and their 65 age-matched female controls. CONCLUSION: Our data indicate that the C677T MTHFR polymorphism does not significantly contribute to the inherited genetic susceptibility to breast and prostate cancer, while we show some evidence for possible genetic contribution of this polymorphism to the development of head and neck carcinoma.     

XPD/ERCC2多态性与晚期结直肠癌对奥沙利铂敏感性关系

目的了解XPD/ERCC2 Lys751Gln（C→A,35931）多态性与晚期结直肠癌对奥沙利铂为主化疗敏感性的关系。方法70例Ⅳ期结直肠癌病人化疗前取静脉血并提取DNA,以real-time PCR法对XPD/ERCC2基因进行单核苷酸多态性（SNP）分型。对病人行奥沙利铂化疗,观察客观缓解率,比较不同基因型与化疗效果的关系。结果XPD/ERCC2 Lys751Gln基因位点在本研究人群中的突变类型及频率为：C/C55.72%,C/A35.71%,A/A8.57%。70例结直肠癌病人化疗有效率（CR＋PR＋SD）为54.29%,C/C与C/A＋A/A基因型在化疗有效组（CR＋PR＋SD）和无效组（PD）之间分布的差异有统计学意义（χ^2=7.926,P〈0.05）。结论XPD/ERCC2 Lys751Gln基因多态性与晚期结直肠癌病人接受奥沙利铂一线化疗后的临床疗效有关。     

Association of transforming growth factor-beta1 gene polymorphisms with genetic susceptibility to nasopharyngeal carcinoma

BACKGROUND: Nasopharyngeal cancer (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Transforming growth factor-beta1 (TGF-beta1) is a multifunctional cytokine, it promotes tumor growth and metastasis in later stages of phase of cancer development. Variations in the DNA sequence in the TGF-beta1 gene may lead to altered TGF-beta1 production and/or activity, and so this can modulate an individual's susceptibility to NPC. To test this hypothesis, we investigated the association of the TGF-beta1 polymorphisms and their haplotypes with the risk of NPC in a Chinese population. METHODS: We analyzed 2 single nucleotide polymorphisms (SNPs) of TGF-beta1 gene promoter -509C/T and 869T/C (Leu10Pro) at exon one in 108 patients with NPC and 120 age- and sex-matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. RESULTS: There were significant differences in the genotype and allele distribution of -509C/T and 869T/C (Leu10Pro) polymorphisms of the TGF-beta1 gene among cases and controls. The -509T and 869C alleles carriers were associated with a significantly increased risk of NPC as compared with the non-carriers (OR=1.64, 95% CI, 1.13-2.39, P=0.009 and OR=1.70, 95% CI, 1.17-2.46, P=0.006, respectively). Consistent with the results of the genotyping analyses, the -509T/869C haplotype was associated with a significantly increased risk of NPC as compared with the -509C/869T haplotype (OR=1.68; 95% CI, 1.14-2.48; P=0.009). CONCLUSION: TGF-beta1 -509C/T and 869T/C polymorphisms, and their haplotypes are significantly associated with the risk of NPC. Our data suggests that TGF-beta1 -509C/T and 869T/C polymorphisms could be used as genetic susceptibility markers of the NPC.     

Genetic variation in interleukin-10 gene and risk of oral cancer

BACKGROUND: Common genetic variants in immune and inflammatory response genes can affect the risk of developing oral cancer. Interleukin-10 (IL-10) is an immunosuppressive cytokine which may facilitate development of cancer by supporting tumor escape from the immune response. Inter-individual variations in IL-10 production were genetically contributed to polymorphisms within IL-10 promoter region. We determined whether single nucleotide polymorphisms (SNPs) at positions -1082 A/G (rs1800870), -819 T/C (rs1800871) and -592 A/C (rs1800872) in the IL-10 gene promoter were involved in predisposing an individual to oral cancer. METHODS: We analyzed 3 SNPS of IL-10 gene promoter in 280 patients with oral cancer and 300 age and sex matched controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) strategy. RESULTS: There were significant differences in the genotype and allele distribution of -1082 A/G (rs1800870) polymorphism of the IL-10 gene among cases and controls. The -1082 G alleles carriers were associated with a significantly increased risk of oral cancer compared with the non-carriers (OR=1.821, 95% CI, 1.329-2.496, P<0.001). Haplotype analysis revealed that the GCC haplotype (defined by SNPs at positions -1082, -819 and -592) of IL-10 gene conveys the highest risk for oral cancer compared with the ATA haplotype (OR=1.716; 95% CI, 1.230-2.395; P=0.001). CONCLUSION: IL-10 gene promoter -1082 A/G (rs1800870) polymorphism, and its haplotype are significantly associated with the risk of oral cancer. Our data suggests that IL-10 gene plays an important role in the development of oral cancer.     

Genetic variations in IL6 associate with intervertebral disc disease characterized by sciatica

Intervertebral disc disease (IDD) characterized by sciatica is a common disorder affecting about 5% of individuals. Environmental factors can predispose to this disease, but IDD has a strong genetic background. Recent evidence suggests that inflammation is one of the key factors in the etiology of IDD. Here, a possible role of the inflammatory mediator genes was studied in 155 patients with IDD-related sciatica and 179 controls. Forty-eight patients were analyzed for mutations in the IL1A, IL1B, IL6 and TNFA genes, and 16 polymorphisms in 10 candidate cytokine genes (IL1A, IL1B, IL1RN, TNFA, IL2, IL4, IL4R, IL6, IL10, IFNG) were genotyped from all subjects. No disease-causing mutations were identified in IL1A, IL1B, IL6 or TNFA. Allele frequencies were, however, significantly different between the two groups for IL6 SNP, T15A in exon 5 (P=0.007). Furthermore, the genotypes AA and AT of the exon 5 SNP were more common in the patients (P=0.011; OR=4.4, 95% CI=1.2-15.7; AR=7.5%, 1.6-13.1%). Haplotypes were then generated for four IL6 SNPs, G-597A, G-572C, G-174C, and T15A in exon 5. Haplotype GGGA was more common in the patients (P=0.011; OR=4.8, 95% CI=1.6-14.5). To evaluate attributable risk, haplotype pairs were assigned for the individuals. The presence of GGGA/GGGA or GGGA/other genotypes had an OR of 5.4 (95% CI=1.5-19.2). Association of GGGA with disease was highly significant (P=0.0033), and the associated AR was 6.8% (1.9-11.5%). These findings support the role of IL-6 genetic variations in discogenic pain.     

Influence of cytotoxic T lymphocyte-associated antigen 4 (CTLA4) common polymorphisms on outcome in treatment of melanoma patients with CTLA-4 blockade

Blockade of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a down-regulator of T-cell activation, can cause cancer regression in patients with metastatic melanoma. However, not all patients respond well to the therapy and some develop severe autoimmune reactions. We hypothesized that common genetic variation in the CTLA4 gene could contribute to response to CTLA-4 blockade and the occurrence of autoimmune reactions. We investigated 7 common single nucleotide polymorphisms, SNPs, (rs733618, rs4553808, rs11571317, rs5742909, rs231775, rs3087243, and rs7565213) in 152 white melanoma patients who received CTLA-4 blockade. Three SNPs were associated with response to therapy: proximal promoter SNPs, rs4553808 [P=0.002; odds ratio (OR) 3.39; 95% confidence interval (CI), 1.62-7.10] and rs11571327 (P=0.02; OR 2.89; 95% CI, 1.23-6.83) and the nonsynonymous SNP rs231775 (Thr17Ala, P=0.009; OR 0.39; 95% CI, 0.18-0.82). A haplotype analysis including the 7 SNPs suggested that the common haplotype, TACCGGG could be associated with no response (P=0.02) whereas the haplotype TGCCAGG (P=0.06; OR 4.13; 95% CI, 1.17-14.5) could be associated with response to the treatment. No significant association was observed for occurrence of severe autoimmune reactions (grade III/IV) either by single SNP or haplotype analyses. Our results suggest that genetic variation in CTLA4 could influence response to CTLA-4 blockade therapy in metastatic melanoma patients, but further studies are necessary to confirm the observed associations.     

Rare variant of hypoxia-inducible factor-1alpha (HIF-1A) and breast cancer risk in Korean women

BACKGROUND: Hypoxia inducible factor 1 alpha (HIF-1A) is activated by low oxygen condition tension, a key regulator of the gene involved in the cellular response to hypoxia. Tumors exhibiting extensive hypoxia are more aggressive than tumors oxygenized better. METHODS: To evaluate the potential role of the polymorphisms of HIF-1A in the etiology of breast cancer, histologically confirmed incident breast cancer cases (n=1599) and control subjects (n=1536) were recruited. RESULTS: Two selected SNPs (Ex15+197C>T and P582S) were not associated with overall breast cancer risk (TT vs. CC: OR=0.9, 95% CI=0.6-1.5, Ser/Ser vs. Pro/Pro: OR=5.5, 95% CI=0.7-45.4, respectively). However, when stratified analyses were performed, significant associations were observed between Ser/Ser genotype at codon 582 and breast cancer risk among women with larger tumor size (>2 cm) (OR=10.1, 95% CI=1.1-91.1) or without lymph node involvement (OR=9.3, 95% CI=1.1-79.4), although confidence intervals were wide. CONCLUSIONS: Our findings support the hypothesis that the HIF-1Alpha P582S variant may confer susceptibility to subgroups of breast cancer in Korean women. However, further study is warranted due to low statistical power caused by very low minor allele frequencies.     

三个候选基因多态性与糖皮质激素性骨质疏松症关联的研究

目的探讨护骨素（OPG）A163G、瘦素受体（LEPR）Gln223Arg和过氧化物酶体增殖物激活受体γ（PPARγ）C161T3个单核苷酸多态性（SNPs）与糖皮质激素性骨质疏松症（GIO）的关系。方法选择哈尔滨医科大学附属第一医院肾内科患者采用限制性片断长度多态性法,在208例健康对照组、168例非GIO组和104例GIO组中分析A163G、Gln223Arg和C161T多态性的基因型分布;应用双能X线骨密度仪（DEXA）测定股骨、腰椎等部位的骨密度。结果在单基因研究中,GIO组患者与健康对照组比较,A163G和C161T基因型和等位基因频率差异有显著意义（P〈0.05）;采用多基因联合分析,OPGGG纯合子中,PPARγTT纯合子GIO患病率显著增高（OR=2.04,95%CI1.26～3.67,P=0.02）。结论OPG A163G和PPAR γC161T多态性可能与GIO的发病相关;在GIO人群中,OPG A163G和PPAR γC161T多态可能有协同作用。     

ERCC1基因多态性与肝癌患者易感性分析

目的探讨切除修复交叉互补基因1(ERCC1)-4533/8092位点单核苷酸多态性(SNPs)与广西壮族人群肝癌易感性之间关系。方法通过聚合酶链反应限制性片段长度多态性(PCR-RFLP)方法检测88例原发性肝癌患者和82例健康对照者的ERCC1-4533/8092基因多态性。结果 ERCC1-4533位点的基因分型在病例组和对照组的频数分布差异无统计学意义(P0.05),ERCC1-8092位点的基因分型在病例组和对照组的频数分布差异具有统计学意义(P0.05)。与携带ERCC1-8092CC基因型的个体相比,携带ERCC1-C8092CA/AA基因型的个体具有更高的肝癌易感性(CA:OR=2.556,95%CI:1.345~4.855;AA:OR=8.667,95%CI:1.000~75.092)。以携带ERCC1-8092C等位基因作为参照,携带ERCC1-C8092A等位基因可以增加原发性肝癌的发病危险性(OR=2.387,95%CI:1.428~3.992)。结论 ERCC1-8092位点基因多态性与广西壮族人群肝癌易感性有关。     

Polymorphisms in second intron of the FGFR2 gene are associated with the risk of early-onset breast cancer in Chinese Han women

Fibroblast growth factor receptor 2 (FGFR2) plays an important role in tumor cell growth, invasiveness, motility, and angiogenesis. Several single-nucleotide polymorphisms (SNPs) in the second intron of the FGFR2 gene are associated with the risk of breast cancer. In this study, we determined whether these SNPs of the FGFR2 gene are associated with early onset of non-familial breast cancer in a Chinese Han population. Recruited were 118 female breast cancer patients who were less than or equal to 35 years of age and without a family history of breast cancer, and 104 age-matched healthy controls. Six SNPs of the second intron of the FGFR2 gene, including rs2981428C/A (i.e., a change at this particular site from nucleotide C to A), rs11200014G/A, rs2981579C/T, rs1219648A/G, rs2420946C/T, and rs2981582C/T, were detected using matrix-assisted laser desorption/ionization mass spectrometry. The data showed that the homozygotes at each minor allele, rs11200014 (AA), rs1219648 (GG), rs2420946 (TT), and rs2981582 (TT), were significantly associated with an increased risk of early-onset non-familial breast cancer. The haplotype containing rs11200014A, rs1219648G, rs2420946T and rs2981582T also exhibited a significantly higher distribution in patients compared to controls (OR=1.784, 95% CI=1.161-2.744). In stratified analyses, each of the above four SNPs conferred a significantly greater risk of estrogen receptor-positive breast cancer, compared to estrogen receptor-negative breast cancer that is more resistant to treatment. Our data demonstrate that these four SNPs of the FGFR2 gene are associated with the risk of breast cancer at a young age in Chinese Han women.     

Association of polymorphisms in the collagen region of human SP-A1 and SP-A2 genes with pulmonary tuberculosis in Indian population.

Surfactant protein A (SP-A) binds to and modulates phagocytosis of Mycobacterium tuberculosis by macrophages. We investigated the relationship between polymorphisms in the collagen regions of SP-A1 and SP-A2 genes and pulmonary tuberculosis. In the present study, seven single nucleotide polymorphisms (SNPs) (4 exonic and 3 intronic) have been identified in the collagen regions of SP-A1 and SP-A2 genes in Indian population. Two intronic polymorphisms, SP-A1C1416T ((p = 0.0000, odds ratio (OR) = 20.767,95% CI: 8.315-OR<51.870) and SP-A2C1382G (p = 0.0054; OR = 3.675, 95% CI: 1.400< OR<9.644), showed significant association with pulmonary tuberculosis (number of patients = 10, number of controls = 7). A redundant SNPA1660G of SP-A2gene showed significant association with pulmonary tuberculosis (number of patients = 17, number of controls = 19, p = 0.0000, OR = 8.94,95% CI: 3.311相似文献