IGF1和IGFBP3多态性与乳腺癌易感性的Meta分析

[目的]综合分析胰岛素生长因子1(Insulin-likegrowthfactor1,IGF1)和胰岛素样生长因子结合蛋白3(Insulin-likegrowthfactorbinding-protein3,IGFBP3)多态性和乳腺癌易感性关系。[方法]采用固定效应和随机效应模型进行Meta分析,研究IGF1(CA)n和IGFBP3(A-202C)多态性和乳腺癌患病风险的关联。[结果]本文研究共包括关于IGF1(CA)n的6个和IGFBP3(A-202C)的4个独立研究。累计病例对照数分别为3053和3391;2793和4136。研究发现,位于IGF1启动子上游1Kb左右的(CA)n重复序列,对比于携带野生型的(CA)19基因型,非携带(CA)19基因型[non19/non19 non19/19]并不增加乳腺癌的发病风险[OR=0.99,95%CI=0.87￣1.12]。对于IGFBP3(A-202C)多态性,我们分别做了显性模型和隐性模型,两个模型OR值分别为1.01(0.91￣1.31)和1.03(0.82￣1.30)。两多态性[IGF1(CA)n和IGFBP3(A-202C)]研究均无发表偏倚(分别为α=2.11,P=0.06和α=-8.40,P=0.47)。[结论]IGF1(CA)n的多态性和IGFBP3启动子区A-202C的多态性改变与乳腺癌的发病风险均不存在明显的关联。     

中国乳腺癌家族BRCA1突变分析

为了探讨中国乳腺癌家族中BRCAl基因突变情况,我们收集了15个乳腺癌家系,共41个对象,其中23例为乳腺癌患者,采用聚合酶链反应-单链构像多态性分析(PCR-SSCP)、直接DNA测序法对BRCA1编码基因进行了全序列分析。结果发现在15个家系中有4例(3种)基因突变,突变比例为26.7％(4/15)。其中一例2228insC为插入突变,致编码子711处蛋白截短;另3例(2种)突变为1884A→T和3232 A→G,分别引起单个氨基酸改变。我们认为BRCA1为家族性乳腺癌的遗传基因;在BRCA1以外还存在其他的乳腺癌易感基因。     

三阴性乳腺癌与BRCA1基因突变风险相关性的Meta分析

目的 对三阴性乳腺癌患者发生BRCA1基因突变风险进行系统综合评价.方法 从PubMed、中国期刊全文数据库、万方、维普、中国生物医学文献数据库中检索相关文献,用比值比(OR)评价三阴性乳腺癌患者发生BRCA1基因突变的风险,用Rev-Man 5.2软件进行Meta分析.结果 共纳入23篇文献,其中三阴性乳腺癌患者1 104例,非三阴性乳腺癌患者4 245例.合并OR及95％ CI为7.67(6.24 ～ 9.42),差异有统计学意义(Z=19.38,P＜0.000 01).在有关人种的亚组分析中,亚洲人合并OR及95％ CI为6.67(4.98 ～8.95),高加索人合并OR及95％ CI为8.83(6.61～11.80),差异有统计学意义(Z=14.74,P＜0.000 01).结论 BRCA1基因在三阴性乳腺癌患者中的突变风险是非三阴性乳腺癌患者的7.67倍.需要大样本的随机对照试验进一步证实,从而使得BRCA1基因突变检测可以常规应用于临床三阴性乳癌患者中.     

中国人群IL-1基因多态性与胃癌发生易感性Meta分析

目的:探讨中国人群IL-1基因多态性与胃癌发生的相关性.方法:通过检索MEDLINE、Embase、Cancerlit、AACR(American association for cancer re-search)、中国生物医学文献数据库(CBM-disc)、中国知网、万方数据库等数据库,纳入16个关于IL-1-31,IL-1B-511,和IL-1RN基因多态性和胃癌相关性的病例对照研究.采用RevMan 4.2.2统计软件进行文献的异质性检验并计算合并效应优势比(OR)和95%可信区间(CI).结果:经筛选纳入16个病例一对照研究,其中包舍2 099例胃癌病例和2 371个正常对照,IL-1B-31C,IL-1B-511T和IL-1 RN 3个位点的OR和C1分剐是[0R=0.98,95%CI(0.72～1.34);P=0.89]、[0R=1.45,95%CI(1.00～2.09);P=0.05]、[0R=1.61,95%CI(0.97～2.67);P=0.07].结论:在中国人群中,IL-1B-31和IL-1RN两位点基因多态性与胃癌发生不存在关联性,IL-1B-511位点基因多态性与胃癌发生易感性相关联.     

DNA双链修复相关基因NBS1的分子改变与肿瘤发生

NBS1基因是一种重要的DNA双链修复相关基因,对维持基因组稳定性及防止细胞癌变具有非常关键的作用.近年研究发现NBS1基因的突变、SNP基因型以及NBS1蛋白表达改变与肿瘤的发生风险和预后有关,本文对此作一综述.     

细胞色素P450 1B1基因多态性与乳腺癌易感性

血清雌激素的浓度是患乳腺癌危险的主要决定因素之一，雌激素在乳腺局部可通过细胞色素氧化酶P4501B1的作用代谢为4羟基雌激素而致癌，本文通过分析雌激素-细胞色素氧化酶P4501B1-乳腺癌之间的相互联系，讨论了CYP1B1的基因多态性与乳腺癌易感性的关系。     

抑癌基因PTEN的突变缺失与乳腺癌

PTEN基因是具有双特异性磷酸酶活性的抑癌基因，大量研究表明，乳腺癌的发生常伴有PTEN蛋白表达的缺失或减弱，提示该基因的突变失活与乳腺癌的发生、发展及预后密切相关。现简要综述PTEN与乳腺癌关系的研究进展。     

中国人群GSTM1基因多态性与肺癌易感性的Meta分析

[目的]探讨中国人群中谷胱甘肽S-转移酶（GSTM1）基因多态性与肺癌易感性的关系。[方法]在Pubmed数据库、CNKI数据库、万方数据库、中国生物医学文献数据库（CBM）中查询文献,时间范围从各数据库建库至2014年5月。采用RevMan 5.1和SAS 9.1.3软件对国内外关于GSTM1基因多态性与肺癌易感性的研究进行合并效应值估计和异质性分析。[结果]37篇文献最终被纳入本次研究。Meta分析结果显示：GSTM1缺失基因型的中国人群患肺癌的风险明显增高（OR=1.45,95%CI：1.30～1.62）。亚组分析发现吸烟与非吸烟的中国人群中GSTM1缺失基因型患肺癌的风险分别为对照组的1.69倍（95%CI：1.39～2.07）和1.46倍（95%CI：1.17～1.82）。在病理类型的亚组分析中,GSTM1缺失基因型的中国人群患鳞状细胞肺癌的风险明显高于对照组（OR=1.35,95%CI：1.13～1.61）。[结论]GSTM1缺失基因型增加中国人群患肺癌的发病风险。     

中国人群COMT Val158Met基因多态性与乳腺癌易感性Meta分析

目的：系统评价中国人群儿荼酚氧位甲基转移酶（catechol-O-methyltransferase,COMT）Vall58Met基因多态性与乳腺癌易感性的关系。方法：在PubMed、MEDLINE、webofScience、Embase、中国期刊全文数据库（CJFD）及万方数据库中检索1999-10-01-2012-01-01发表的所有有关中国人群COMTVall58Met基因多态性与乳腺癌易感性关系的相关文献,并按STREGA原则对文献进行筛选、评价。纳入文献均为病例对照研究,对照群体基因型分布均符合H-W遗传平衡定律。应用Stata 12．0软件进行Meta分析,计算合并0R值及95％CI,并进行敏感性分析和发表偏倚的估计。结果：按照入选标准,有11项病例对照研究纳入,包括乳腺癌患者3184例,健康对照4065例。Meta分析结果显示,与基因型Val／Val（GG）、Val／Met（GA）比较,基因型Met／Met（AA）均增加中国人群罹患乳腺癌的风险[OR=1．55,95％CI：1.03～2．33,P=0．035;OR-1．63,95％CI：1．10～2．42,P=0．015];在隐性效应模型（Met／Met／vs Val／Val＋Val／Met）中,基因型Met／Met（AA）增加中国人群罹患乳腺癌的风险,0R-1．59,95％CI：1．07～2．36,P=0．021。与等位基因Val（G）比较,等位基因Met（A）不增加中国人群罹患乳腺癌的风险,OR=1．12,95％CI：0．96～1．32,P=0．157。结论：COMTVall58Met基因多态性与中国人群乳腺癌易感性相关,基因型Met／Met（AA）增加中国人群罹患乳腺癌的风险。     

乳腺癌转移抑制基因1表达与肿瘤发生发展相关性的Meta分析

目的 探讨乳腺癌转移抑制基因1(BRMS1)的表达与肿瘤发生发展的相关性,为预测肿瘤的发生和转移提供依据.方法 从PubMed、EMBase、中国期刊全文数据库(CNKI)、万方医药期刊全文数据库、维普中文科技期刊全文数据库等检索BRMS1与肿瘤发生的临床研究文献,用比值比(OR)评价肿瘤发生与BRMS1阳性表达率的关系.原始数据汇总后用RevMan 5.3软件进行统计分析.结果 共纳入文献27篇,其中肿瘤病例组2 282例,非肿瘤对照组1 236例,合并OR值为0.10,95％ CI为0.08～0.14,BRMS1在两组中的表达差异有统计学意义(Z=15.37,P＜0.000 01).在有关肿瘤类型亚组中,乳腺癌合并OR值为0.10,95％ CI为0.05～0.20,BRMS1在乳腺癌和非乳腺癌组织中的表达差异有统计学意义(Z=6.18,P＜0.000 01).结论 BRMS1的阳性表达与肿瘤的发生呈负相关,同时BRMS1的阳性表达与乳腺癌的发生也呈负相关.BRMS1在肿瘤组织中低表达或者缺失,其有望作为预测肿瘤发生和转移的生物标志物.     

Germline 657del5 mutation in the NBS1 gene in breast cancer patients

In this report the proportion of consecutive and familial breast cancer cases harboring the 657del5 of exon 6 of the NBS1 gene was determined to assess whether it is associated with the increased risk of breast cancer development. The study consisted of 3 groups of patients: a series of consecutive 150 patients with histologically confirmed breast cancer, diagnosed under the age of 50 in the city of Szczecin; a series of 80 breast cancer patients with a family history of breast cancer in their first-degree relatives; and a series of 530 consecutive individuals without the diagnosis of breast cancer selected at random by family doctors from the city of Szczecin. Molecular examination included allele-specific PCR assay for the common Slavic NBS1 mutation (657del5), LOH analysis using denucleotide CA repeat microsatellite markers, haplotype analysis and sequencing. The NBS1 founder mutation was detected in 2 of 150 (1.3%) consecutive breast cancer cases diagnosed under the age of 50 years; in 3 of 80 familial breast cancer cases (3.7%); and in 3 of 530 individuals (0.6%) from the general population. Examination of tumor DNA from patients with the NBS1 mutation (groups A and B) revealed loss of heterozygosity (LOH) in all cases. Additional haplotype analysis revealed that allelic loss affects specifically wild-type alleles. The majority of probands with breast cancer and the NBS1 mutation had a positive family history of breast cancer in their first-degree relatives. It appears that the 657del5 mutation in exon 6 of the NBS1 gene is responsible for the occurrence of a small but significant proportion of familial breast cancer patients.     

Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland

Recent studies have demonstrated that heterozygous carriers of the NBS1 657del5 mutation have an increased risk for familial and bilateral breast cancer, but similar studies in consecutive breast cancer patients were inconclusive. Here, in a study of 562 nonselected breast cancer patients from Central Poland, we found 11 (1.96%) 657del5 mutation carriers vs. 3.47 expected (OR 3.21, 95%CI: 1.36-7.61, p = 0.0107) and only 9 (1.6%) carriers of the 5382insC mutation of the BRCA1 gene, most frequently found among breast cancer patients in Poland. No carriers of R215W, another pathogenic mutation of the NBS1 gene, were found in the present study. All carriers of the 657del5 mutation had sporadic breast tumors while 5 of 9 5382insC carriers had a family history of breast/ovarian cancer or bilateral breast carcinoma. In the pooled group of patients from the present and our previous study, carried out also in patients from Central Poland, we obtained the following risk estimates (OR) for 657del5 carriers, as related to the age at breast cancer diagnosis: < 40 years: 8.36; (95%CI: 2.57-27.27) p = 0.0003; < 50 years: 4.27 (95%CI: 1.67-10.89) p = 0.003; > or = 50 years: 2.40 (95%CI: 0.91-6.35) p = 0.1250; all ages: 3.13 (95% CI: 1.40-7.00) p = 0.0066. These findings demonstrate conclusively that NBS1 657del5 mutation carriers have a significantly, though moderately increased, age-related risk of breast cancer, and imply that in populations with a high 657del5 carrier frequency this mutation may contribute substantially to the overall incidence of breast cancer, particularly in younger age groups.     

NBS1 657del5 mutation may contribute only to a limited fraction of breast cancer cases in Russia

The gene for Nijmegen chromosomal breakage syndrome (NBS1) plays a role in a variety of processes protecting chromosomal stability. Recently, it was suggested in a Polish case-control study that the founder hypomorphic mutation in NBS1, 657del5, which occurs in approximately 0.5% of Slavic subjects, may be associated with an increased risk of breast cancer (BC). We attempted to validate these findings in Russian subjects, who are also of Slavic descent. Heterozygous carriers for the 657del5 mutation were detected in 2 of 173 (1.16%) bilateral breast cancer cases, 5 of 700 (0.71%) unilateral breast cancer patients, 2 of 348 (0.57%) healthy middle-aged females and in 0 of 344 elderly tumor-free women. The difference between the "extreme" cohorts, i.e., biBC patients vs. elderly controls, approached the formal limit of statistic significance (p=0.046). LOH at NBS1 was detected in only 3 of 5 available breast tumors from NBS1 657del5-carriers. In 2 of these tumors, the loss involved the mutant NBS1-allele. Overall, our data suggest that the NBS1 657del5 allele may contribute only to a limited fraction of breast cancer cases in Russia.     

Increased risk of gastrointestinal lymphoma in carriers of the 657del5 NBS1 gene mutation

The NBS1 gene mutation, 657del5, frequent in the Slavic populations of Central Europe, is found in most patients with Nijmegen breakage syndrome (NBS), a recessive autosomal disorder with a very high incidence of non-Hodgkin lymphoma (NHL). We have previously described 2 heterozygous 657del5 mutation carriers among 42 adult NHL probands from Central Poland. Here we report 6 additional carriers of the 657del5 mutation and 2 carriers of the pathogenic NBS1 R215W mutation, among 186 other NHL patients also from Central Poland. The 657del5 carrier frequency in the pooled group of these 228 patients was significantly higher than in population controls (OR 5.85, 95% CI: 2.29-15.00, p = 0.0001). Interestingly, 4 of these carriers were found among 37 patients with gastrointestinal lymphoma (OR 19.52, 95% CI: 5.82-65.42, p = 0.0002). These findings imply that heterozygous NBS1 germline mutations may contribute significantly to the overall incidence of NHL, especially of the gastrointestinal tract, in Central Europe.     

Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies

Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.     

家族性乳腺癌家系成员乳腺癌易感基因突变的研究

目的研究河北省地区家族性乳腺癌家系中的患者及健康一级亲属乳腺癌易感基因1（BRCAl）和乳腺癌易感基因2（BRCA2）突变位点及携带情况。方法研究对象为2002年6月至2008年5月河北医科大学第四医院接诊的乳腺癌患者及其亲属,分别来自12个独立的汉族家族性乳腺癌家系,该家系中有2个及2个以上一级或二级亲属乳腺癌患病史,研究病例包括13例患者及46例健康一级亲属,共59例样本。由外周血提取基因组DNA,采用聚合酶链反应一单链构象多态性分析（PCR—SSCP）和基因测序技术对国内外报告中常见的4个BRCAl／BRCA2突变热点区域（BRCAl：外显子2、11、20;BRCA2外显子11）进行检测。结果发现1个BRCAl突变位点（4193insA）和1个BRCA2突变位点（5329insT）,全部为移码突变;发现4个变异位点（BRCAl：4165T〉A、287G〉C,BRCA2：6251G〉T、5416C〉A）,4193insA、5329insT、287G〉C携带者的家系中均有3例乳腺癌患者。结论BRCAl（4193insA）、BRCA2（5329insT）以及BRCAl：4165T〉A、287G〉C和BRCA2：6251G〉T、5416C〉A可能是河北省家族性乳腺癌相关性突变位点,其携带者家系中乳腺癌发病率明显升高,建议对其一级亲属密切随访或尽早进行手术或药物干预。     

Increased cancer risk of heterozygotes with NBS1 germline mutations in Poland

It has been suggested based on familial data that Nijmegen breakage syndrome (NBS) heterozygotes have an increased risk of malignant tumors. We found 15 carriers of the 657del5 mutation and 8 carriers of the R215W molecular variant of the NBS1 gene among 1,289 consecutive patients from Central Poland with various cancers and only 10 and 4 such carriers, respectively, in 1,620 controls from this region. Most of the 657del5 mutation carriers were found among patients with melanoma (4/105), non-Hodgkin lymphoma (2/42) and breast cancer (4/224) and of the 234 patients with colorectal carcinoma 3 carried the 657del5 mutation and 3 others the R215W molecular variant. The frequencies of 657del5 mutation carriers among patients with melanoma and non-Hodgkin lymphoma and of R215W carriers in patients with colorectal cancer were significantly higher than in controls (p < 0.01, < 0.05 and < 0.05 respectively). The pooled frequencies of 657del5 and R215W mutations in all cancer patients were also significantly higher than in controls (p < 0.05). Two carriers of the 657del5 mutation had second primary tumors. Malignant tumors among parents and siblings of 657del5 mutation carriers (14/77) were twice more frequent than in population controls. Three carriers of this mutation (2 probands with melanoma) reported melanoma in relatives. These results suggest strongly that NBS1 heterozygosity may be associated with elevated risk of some cancers. Larger studies are needed to evaluate the impact of the high frequency of germline NBS1 mutations on the cancer burden in the Slav populations.     

乳腺癌易感基因突变对前列腺癌易感性的影响

目的:用 Meta 分析评价乳腺癌易感基因（BRCA）突变对前列腺癌易感性的影响。方法:通过计算机检索PubMed、Embase、Cochrane图书馆、Web of Science、Springer Link等数据库,对纳入的研究运用Revman 5．3软件以及stata 14.0软件进行 Meta 分析。结果:共纳入 23 篇文献, 共 47 726 例患者, 其中BRCA1基因突变人群5 745例,BRCA2基因突变人群5 127例。Meta 分析结果显示:BRCA1基因对前列腺癌易感性(OR:1.62,95%CI:0.83～3.15,P=0.16)、Gleason评分(OR:1.39,95%CI:0.89～2.15,P=0.15)、T分期(OR:0.84,95%CI:0.44～1.58,P=0.59)、总生存时间(OR:1.12,95%CI:0.64～1.95,P=0.69)无统计学差异;在BRCA2基因对前列腺癌易感性(OR:2.24,95%CI:1.70～3.44,P＜0.000 01)、Gleason评分(OR:4.34,95%CI:3.06～6.15,P＜0.000 01)、T分期( OR:2.33,95%CI:1.09～4.96,P=0.03)、总生存时间(OR:1.53,95%CI:1.37～1.71,P＜0.000 01)有显著性差异。结论:BRCA2基因突变的人群患前列腺癌的风险以及预后明显比非突变人群的要高。     

Current Evidence on the Relationship Between Two Polymorphisms in the NBS1 Gene and Breast Cancer Risk: a Meta-analysis

Introduction: Published studies on the association between Nijmegen breakage syndrome 1(NBS1) genepolymorphisms and breast cancer risk have been inconclusive, and a meta-analysis was therefore performed forclarification. Methods: Eligible articles were identified by a search of MEDLINE and EMBASE bibliographicdatabases for the period up to March 2012. The presence of between-study heterogeneity was investigated usingthe chi-square-based Cochran’s Q statistic test. When there was statistical heterogeneity, the random effectsmodel was chosen; otherwise, fixed effects estimates were reported as an alternative approach. Results: A totalof 11 eligible articles (14 case-control studies) were identified, nine case-control studies were for the 657del5mutation (7,534 breast cancer cases, 14,034 controls) and five case-control studies were for the I171V mutation(3,273 breast cancer cases, 4,004 controls). Our analysis results indicated that the 657del5 mutation was associatedwith breast cancer risk (carriers vs. non- carriers: pooled OR =2.63, 95% CI: 1.76-3.93), whereas the I171Vmutation was not (carriers vs. non-carriers: pooled OR =1.52, 95% CI: 0.70-3.28). Conclusion: The presentmeta-analysis suggests that the 657del5 gene mutation in the NBS1 gene plays a role in breast cancer risk, whilethe I171V mutation does not exert a significant influence     

JAK2基因突变与慢性髓系白血病 易感性的meta 分析

目的：探讨JAK2基因突变与慢性髓系白血病（CML）的关系。方法：检索中国知网（CNKI）、维普（VIP）、万方、PubMed、Web of Science、CBM数据库中关于JAK2突变与CML关系的文章。检索时间截至2018年9月,由两位研究者独立按照纳入与排除标准筛选文献,提取资料后,用纽卡斯尔-渥太华量表（NOS）评分进行质量评价。采用Stata 11.0、RevMan 5.3软件进行meta分析。结果：共纳入15篇文章,包含总病例数1 684例,JAK2基因突变104例（突变位点分别位于第12和第14号外显子编码序列的第1 849位碱基G被T取代）。Meta分析结果显示CML患者的JAK2基因突变率为0.08[95% CI （0.05,0.11）],亚组分析显示费城染色体（Ph）和JAK2是否突变、不同地区的突变分布、外显子的突变位点是异质性的主要来源。结论：慢性髓系白血病细胞JAK2基因外显子12和14突变、突变体JAKV617F的存在可能促使CML的发生。