湖北地区人群乳腺癌易感基因FGFR2多态性研究

目的:探讨湖北地区人群成纤维细胞生长因子受体-2基因(FGFR2)第2内含子单核苷酸多态性(SNP)与乳腺癌易感性的关系。方法:采用PCR及DNA测序方法,对汉族204例女性乳腺癌患者(乳腺癌组)和192名正常女性(对照组)FGFR2基因第2内含子区的2个多态性位点(rs2981582和rs10510097)进行分析,计算基因型和等位基因频率。结果:汉族人群正常对照组FGFR2基因第2内含子SNP位点rs2981582的C/C、C/T和T/T基因型频率分别为31.82%、54.54%和13.64%,而乳腺癌组分别为34.02%、53.61%和12.37%,其基因型和等位基因频率两组相比差异均无统计学意义,P值均>0.05;另一位点rs10510097正常对照组的C/C、C/T和T/T基因型频率分别为60.00%、33.33%和6.67%,乳腺癌组分别为55.31%、36.87%和7.82%,其基因型和等位基因频率两组相比差异均无统计学意义,P值均>0.05。结论:湖北地区人群FGFR2第2内含子2个多态性位点和乳腺癌并无明显相关性。     

FGFR1基因单核苷酸多态性与中国北方汉族女性乳腺癌发病风险及临床病理特征的关系

目的:探究成纤维生长因子受体1（fibroblast growth factor receptor-1,FGFR1)基因单核苷酸多态性与中国北方汉族女性乳腺癌发病风险和临床病理特征的相关性。方法:采用多重单碱基延伸单核苷酸多态性分型技术检测747例乳腺癌患者和716例健康女性人群FGFR1基因rs13317和rs3213849多态位点基因型,并比较不同基因型与乳腺癌发病风险和临床病理特征的关系。结果:FGFR1基因rs13317和rs3213849多态位点基因型频率在乳腺癌组和对照组中的分布无统计学差异(P＞0.05)。与TT基因型携带者相比,rs13317位点的CT基因型、CC基因型和CT+CC基因型携带者与乳腺癌发病风险无关(P=0.464、P=0.136、P=0.103)。与GG基因型携带者相比,rs3213849位点的GA基因型、AA基因型和GA+AA基因型携带者与乳腺癌发病风险无关(P=0.642、P=0.222、P=0.416)。临床病理分析结果显示,rs13317位点多态性与乳腺癌患者的临床分期、肿瘤大小、组织学分级、淋巴结转移、ER、PR、HER2、Ki67及p53无关(P＞0.05)。在共显性模型下,rs3213849位点在Ki67分布上可能存在差异(P=0.055);在显性模型下,rs3213849位点与Ki67表达情况具有相关性(P=0.023),与其他临床病理因素之间均不相关(P＞0.05)。结论:在目前的样本条件下,FGFR1基因rs3213849位点与Ki67表达可能相关,而rs13317和rs3213849多态性与中国北方汉族女性乳腺癌易感性及其他临床病理特征之间无明显相关性。     

FGFR2基因多态性与乳腺癌相关性

成纤维细胞生长因子2型受体（FGFR2）在细胞的增殖、分化中起重要作用,其基因具有遗传多态性。近年研究表明,这种多态性与乳腺癌的发病风险以及临床病理因素具有相关性。     

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。     

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。     

中国人群FGFR2基因多态性与乳腺癌易感相关性研究的Meta分析

目的系统评估成纤维细胞生长因子受体2(fibroblast growth factor receptor 2,FGFR2)基因内含子的3个单核苷酸位点rs2981582、rs1219648和rs2420946多态性与中国人群乳腺癌的易感性的关系。方法计算机检索PubMed、Embase、Cochrane library、中国知网、维普、万方数据库及中国生物医学文献数据库中,2014-06-01之前关于FGFR2基因内含子的3个单核苷酸位点rs2981582、rs1219648和rs2420946多态性与中国人群乳腺癌易感性的相关研究,按纳入与排除标准筛选文献、提取资料并评价纳入研究的质量后,采用Stata 12.0软件进行Meta分析,计算合并OR值及其95%CI,并进行发表偏倚评估及敏感性分析。结果共纳入18篇文献,包括14 568例患者和12 864名对照。Meta分析结果显示,FGFR2rs2981582、rs1219648和rs2420946基因多态性与中国人群乳腺癌有显著相关性。以地域进行亚组分析,rs2981582的T等位基因在南方人群(OR=1.13,95%CI:1.06~1.22,P=0.001)和北方人群(OR=1.26,95%CI:1.06~1.49,P=0.008)中与乳腺癌显著相关;rs2420946的T等位基因在南方人群(OR=1.15,95%CI:1.08~1.23,P<0.05)中与乳腺癌显著相关,北方人群中差异无统计学意义(OR=1.03,95%CI:0.87~1.22,P=0.695);rs1219648的G等位基因在南方人群(OR=1.19,95%CI:1.10~1.28,P<0.05)和北方人群(OR=1.17,95%CI:1.00~1.37,P=0.05)中与乳腺癌有显著相关。结论 FGFR2rs2981582、rs1219648和rs2420946基因多态性与中国人群乳腺癌易感性显著相关,但以地域进行亚组分析时则表现有差异。     

江西汉族女性BRCA2基因单核苷酸多态性与散发性乳腺癌易感相关性研究

目的:探讨BRCA2基因单核苷酸多态性(SNP)与江西汉族女性散发性乳腺癌易感性的关系。方法:利用SequenomMassArrayiPLEX GOLD系统对江西南昌大学第一附属医院散发性乳腺癌患者152例和健康对照组165名的BRCA2基因编码区3个单核苷酸多态性位点(rs766173,rs144848,rs1801426)进行基因型检测,非条件Logistic回归分析。结果:rs766173位点基因型和等位基因型频率分布差异均有统计学意义(χ2=4.602,P=0.032;χ2=4.097,P=0.043)。相对TT基因型,TG杂合型与TG+GG型均能显著性增加乳腺癌发生的危险性,OR值(95%CI)分别为1.971(1.060~3.666)和1.934(1.052~3.555),P分别为0.032和0.034。相对等位基因T,等位基因G为易感等位基因,OR值为1.792(95%CI=1.012~3.172,P=0.045)。另外两个位点rs144848和rs1801426多态性分布频率在乳腺癌组和对照组之间差异无统计学意义。结论:rs766173位点基因多态性与江西地区汉族女性散发性乳腺癌易感性相关,另外两个多态性位点rs144848和rs1801426与江西地区女性散发性乳腺癌易感性无关。     

FGFl9和FGFR4在肿瘤中作用的研究进展

FGFl9和FGFR4的表达与肿瘤发生有关，FGFR4基因单核苷酸多态性与肿瘤的发生、侵袭转移和预后密切相关。通过阻断FGFl9和FGFR4的相互作用可以抑制肿瘤生长，这为肿瘤的生物治疗提供了有效的靶标。作者总结国内外对FGFl9和FGFR4在肿瘤中作用的研究进展，综述其在肿瘤的发生、浸润、转移、预后和治疗上的作用。     

CYPlAl和CYPlA2基因多态性与汉族女性乳腺癌的关系

目的 探讨CYP1A1基因MspⅠ位点与CYP1A2基因C734A位点多态性与汉族女性乳腺癌的关系.方法 应用聚合酶链反应-限制性片段长度多态性技术和限制性核酸内切酶酶切的方法,检测2011年9月至2012年8月在四川省医学科学院四川省人民医院确诊的144例女性乳腺癌患者（乳腺癌组）和152例同期健康体检正常女性（对照组）CYP1A1基因MspⅠ与CYP1A2基因C734A多态性位点的基因型,用χ2检验比较两组等位基因频率的差异.结果 在乳腺癌组与对照组中,CYP1A1基因MspⅠ位点T等位基因频率分别为0.73和0.65,两者差异有统计学意义（χ2=4.94,P=0.03）,C等位基因与T等位基因相比,乳腺癌发病风险OR为0.67 （95%CI：0.47～0.96）;CYP1A2基因C734A位点C等位基因频率分别为0.26和0.29,两者差异无统计学意义 （χ2=0.63,P=0.43）.将乳腺癌组按照ER、PR表达与否进一步分组后,CYP1A1基因MspⅠ与CYP1A 2基因C734A 2个多态性位点的等位基因频率在ER（＋）与ER（-）组之间以及PR（＋）与PR（-）组之间差异均无统计学意义[ER（＋）组比ER（-）组：χ2=0.34、0.01;PR（＋）组比PR（-）组：χ2=0.60、0.68;P均〉0.05].结论 汉族女性CYP1A1基因MspⅠ位点多态性与乳腺癌相关联.     

FGFR2基因多态性与乳腺癌的相关性研究

目的:探讨成纤维细胞生长因子受体2基因(FGFR2)第二内含子单核苷酸多态性在女性群体中的频率分布及其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-限制性片段长度多态性(PCR-RFLP)方法结合琼脂糖凝胶电泳技术,对106例女性乳腺癌患者(乳腺癌组)和116例正常女性(对照组)对照进行检测,分析两组贵州地区人群FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946和rs2981579的基因及基因型的分布情况.结果:乳腺癌组FGFR2基因单核苷酸多态性位点rs2420946的基因型(AA,AG.CG)频率分别为15.09%、48.11%、36.79%,对照组为18.10%、43.97%、37.93%;乳腺癌组与对照组A等位基因频率分别为39.15%和40.09%,G等位基因频率分别为60.85%和59.91%;两组人群分别进行比较,基因型及等位基因频率分布的差异均无统计学意义(P>0.05);FGFR2基因rs2981579的基因型(CC,CT,TT)频率在乳腺癌组分别为30.19%、45.28%、24.53%,对照组为27.59%、48.28%、24.14%;乳腺癌组与对照组c等位基因频率分别为52.83%和51.72%,T等位基因频率分别为47.17%和48.28%;两组人群分别进行比较,基因型频率与等位基因频率分布的差异均无统计学意义(P>0.05).结论:FGFR2基因第二内含子的两个单核苷酸多态性位点rs2420946及rs2981579在乳腺癌及对照人群中基因型频率与等位基因频率分布差异均无统计学意义,提示两个位点的多态性与乳腺癌无明显相关性.     

FGFR2 gene polymorphisms are associated with breast cancer risk in the Han Chinese population

Aims and background: Breast cancer is one of the most common neoplasms among women in many developing countries including China, and is the leading cause of female cancer-related deaths worldwide. Methods: In the current study, we analyzed the relationship between 14 tag single-nucleotide polymorphisms (tSNPs) and breast cancer risk in the Han Chinese population including 185 breast cancer patients and 199 healthy women controls on the different types of breast cancer and menopausal status. Results: Overall, we found rs2981579 in the FGFR2 gene, and rs2380205 were associated with breast cancer susceptibility.Conclusions:These findings indicate that FGFR2 was associated with breast cancer risk in the Han Chinese population, support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations.     

TOX3基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险关联的研究

目的:探讨TOX3基因单核苷酸多态与中国北方汉族绝经前妇女乳腺癌风险的关系。方法:采用多重单碱基延伸单核苷酸多态性分型技术(Snapshot)分析方法,检测280例绝经前的乳腺癌患者和287例绝经前的正常对照者TOX3基因rs3803662和rs12443621多态性位点基因型,并比较不同基因型与乳腺癌风险的关系。结果:TOX3基因rs3803662和rs12443621多态性位点基因型频率,在乳腺癌病例组和对照组之间差异无统计学意义,P值分别为0.718和0.340。Logistic回归分析结果显示,对于rs3803662位点,与GG基因型相比,GA、AA和GA+AA基因型与乳腺癌的危险性无关(OR=0.846,95%CI:0.489～1.463,P=0.549;OR=0.802,95%CI:0.470～1.368,P=0.418;OR=0.821,95%CI:0.492～1.368,P=0.449);对于rs12443621位点,与GG基因型相比,GA、AA和GA+AA基因型与乳腺癌的危险性无关(OR=0.755,95%CI:0.518～1.099,P=0.755;OR=0.850,95%CI:0.528～1.368,P=0.504;OR=0.781,95%CI:0.548～1.112,P=0.170)。结论:在目前样本条件下,TOX3基因rs3803662和rs12443621位点多态性与中国北方汉族绝经前妇女乳腺癌易感性之间无明显关联。     

Association of FGFR3 and FGFR4 gene polymorphisms with breast cancer in Chinese women of Heilongjiang province

Background

The fibroblast growth factor (FGF) receptor pathway is activated in many tumors. FGFR2 has been identified as a breast cancer susceptibility gene. Common variation in other FGF receptors might also affect breast cancer risk. We carried out a case-control study to investigate associations of variants in FGFR3 and FGFR4 with breast cancer in women from Heilongjiang Province.

Methods

SNP rs2234909 and rs3135848 in FGFR3 and rs1966265 and rs351855 in FGFR4 were successfully genotyped in 747 breast cancer patients and 716 healthy controls using the SNaPshot method. The associations between SNPs and breast cancer were examined by logistic regression. The associations between SNPs and disease characteristics were examined by chi-square tests or one-way ANOVA as needed.

Results

The minor alleles of rs1966265 and rs351855 in FGFR4 were strongly associated with breast cancer in the population, with odds ratios of 1.335 (95%CI = 1.154-1.545) and 1.364 (95%CI = 1.177-1.580), respectively. However, no significant associations were detected between other SNPs and breast cancer. Analyses of the disease characteristics showed that SNP rs351855 was associated with lymph-node-positive breast cancer with a dose-dependent effect of the minor allele (P = 0.008).

Conclusions

SNPs rs1966265 and rs351855 in FGFR4 were associated with breast cancer in a northern Chinese population.     

Low‐risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients

To validate common low‐risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy women by MALDI‐TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30‐1.59, p‐value = 1.24 × 10⁻¹²) and for TNRC9 (OR = 1.33, 95% CI 1.19‐1.46, p‐value = 1.54 × 10⁻⁷). Most intriguing, however, were the ORs for homozygous carriers from high‐risk families for FGFR2 (OR = 2.05, 95% CI 1.68–2.51, LSP1 (OR = 0.49, 95% CI 0.28–0.86) and TNRC9 (OR = 1.62, 95% CI 1.27–2.07). Moreover, the additional validation of 99 CGEMS‐SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61–0.87, p‐value = 5.23 × 10⁻⁴⁾. Finally, we provide evidence for the first time that a low‐risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06–1.66; p‐value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.     

乳腺癌易感基因单核苷酸多态性与激素受体状态关联性研究现状

目的回顾和总结国内外关于乳腺癌易感基因的单核苷酸多态性（single nucleotide polymorphism,SNP）与乳腺癌患者体内激素受体（estrogen receptor,ER）状态的关联性研究。方法应用Pubmed和CNKI期刊全文数据库检索系统,以＂乳腺癌、易感基因、单核苷酸多态性（SNP）和激素受体状态＂作为关键词,检索2009-01-2014-05相关文献。纳入标准：1）乳腺癌易感基因位点的相关研究和进展;2）乳腺癌易感基因的SNP和激素受体状态的研究现状和进展;根据纳入标准,符合分析的文献共42篇。结果一些易感基因位点的SNP与激素受体阳性乳腺癌易感性相关,如FGFR2、MP3K1的1p11.2等;而另一些位点如19p13.11和8q24的基因多态性则与激素受体阴性乳腺癌的发病相关;TOX3基因多态性则与激素受体阳性及阴性乳腺癌的发病均相关,且与ER阳性乳腺癌的发病相关性更强。因为乳腺癌的发生和发展是多基因多阶段协同作用的结果,在不同种族、不同地区、不同环境中所开展的研究,不同的SNP位点对乳腺癌的患病风险及激素受体状态的影响不尽相同。结论激素受体状态在乳腺癌的免疫分型中起主要作用,研究乳腺癌易感基因的SNP与激素受体状态的关联性,有助于进一步了解乳腺癌的发病机制、肿瘤转归,有望在关于SNP与乳腺癌分子分型的相关研究上取得新的突破。     

Association of rs1219648 in FGFR2 and rs1042522 in TP53 with Premenopausal Breast Cancer in an Iranian Azeri Population

Breast cancer is the most common cancer among women in the world. In Iran, the incidence of breast canceris on the increase. We here studied the association of rs1219648 in FGFR2 and rs1042522 in TP53 and theirinteraction in development of early onset sporadic breast cancer in Iranian Azeri population to evaluate epistaticeffects on the risk of mammary neoplasia. We genotyped the two polymorphisms in 100 women with early onsetbreast cancer and 100 healthy women by PCR-RFLP. Allele frequency differences were tested using chi2-test with95% confident intervals. Our results indicated a statistically significant association (p<0.05) between rs1219648,but not rs1042522, and risk of breast cancer. We also found that the combination of FGFR2 major genotypeand TP53 hetero genotype had protective effects against breast cancer , while the hetero allele of FGFR2 incombination with the minor genotype of TP53 was associated with a high risk. This study revealed an importantcrosstalk between two polymorphisms in FGFR2 and TP53 in development of breast cancer. These candidatesrisk variants should be further evaluated in studies with a larger sample size.     

Transforming properties of TC-1 in human breast cancer: interaction with FGFR2 and beta-catenin signaling pathways

Breast cancer development is associated with gene amplification and over expression that is believed to have a causative role in oncogenesis. Previous studies have demonstrated that over expression of TC-1(C8orf4) mRNA occurs in approximately 50% of breast cancer cell lines and primary tumor specimens. Here, we show that TC-1 has transforming properties in human mammary epithelial (HME) cells and its expression is mechanistically linked to FGFR signaling cascades. In vitro experiments demonstrate that TC-1 over expression mediates both anchorage-independent and growth factor-independent proliferation of HME cells. TC-1 was down regulated by the FGFR inhibitor PD173074 in the breast cancer cell line SUM-52 that also has an FGFR2 gene amplification and over expression. Furthermore, forced expression of FGFR2 in HME cells increased the level of expression of endogenous TC-1 mRNA. TC-1 has been implicated as a modulator of Wnt/beta-catenin signaling in 293 cells and in gastric cancer cells. However, while we did find increased expression of a subset of beta-catenin target genes in TC-1 over expressing cells, we did not find an association of TC-1 with global expression of beta-catenin target genes in our cells. Taken together, our data suggest that TC-1 over expression is transforming and may link with the FGFR pathway in a subset of breast cancer.