2型糖尿病易感基因TCF7L2、IGF2BP2多态性与汉族女性乳腺癌发病风险的关联研究
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摘要
乳腺癌是女性常见恶性肿瘤之一，中国近年来乳腺癌的发病率以3%以上的速度逐年增加，已高居女性恶性肿瘤的第一位。2型糖尿病是由遗传和环境因素共同作用而引起的以慢性血糖升高为主要表现的代谢综合症。胰岛素缺乏和胰岛素作用障碍单独或同时引起糖类、脂肪、蛋白质、水和电解质等的代谢紊乱。近年来全球的糖尿病患病率迅速增加，中国已经成为全世界糖尿病患病率增加最快的国家之一，到2020年我国糖尿病人数将超越印度成为世界第一。Meta分析显示，2型糖尿病患者发生乳腺癌的相对风险约为普通人群的1.2～1.5倍。本课题第一部分通过对80例乳腺癌合并2型糖尿病患者与160例乳腺癌非糖尿病患者病历资料进行回顾性分析,探讨了2型糖尿病对乳腺癌临床病理特征及预后的影响。
目前越来越多的研究表明2型糖尿病与乳腺癌存在着复杂的联系，但具体机制还不是很明确。基因突变被认为与两种疾病均有关，而且相同的基因突变有可能部分解释2型糖尿病与乳腺癌之间的相关性。为了探讨2型糖尿病的易感基因变异是否会增加患乳腺癌的风险，本研究选择了两个2型糖尿病易感基因（TCF7L2，IGF2BP2）的3种寡核苷酸多态性（singlenucleotide polymorphisms，SNP) TCF7L2基因rs7903146、rs12255372和IGF2BP2基因rs4402960，探讨了它们对患乳腺癌风险的影响。转录因子7类似物2（transcription factor7-like2，TCF7L2），又称T细胞转录因子-4（TCF4），其基因位于10q25.2。该基因编码一种含有高迁移率组（HMG）盒的转录因子，参与Wnt/β-catentin信号通路。多项全基因组关联分析研究显示，TCF7L2是2型糖尿病的易感基因之一。Barbara[41]等通过TaqMan等位基因分布技术检测了TCF7L2rs12255372变异在家族性乳腺癌中的作用。研究表明，TCF7L2rs12255372可能影响家族性乳腺癌发病风险。Naidu等[42]对来自医院的马来群岛人群中的387名乳腺癌患者及252名没有任何肿瘤病史的健康女性采用PCR-RFLP方法检测TCF7L2基因多态性的基因型。rs7903146位于TCF7L2基因的3号内含子上，存在CC、CT和TT三种基因型,危险等位基因是T。乳腺癌患者中rs7903146（T）等位基因频率明显高于正常人。CT或TT基因型与乳腺癌风险无关。然而，携带T基因型（CT+TT）或T等位基因的女性表现出了明显增加的乳腺癌风险。rsl2255372位于TCF7L2基因的4号内含子，存在GG、GT和TT3种基因型，危险等位基因是T。GT杂合子或TT纯合子和携带T基因型或T等位基因均与乳腺癌风险无关。rs7903146（T）与淋巴结转移有关，但是rs12255372T等位基因与临床病理特征无关。总之，TCF7L2基因rs7903146（T）变异可能增加乳腺癌风险，有可能成为乳腺癌的候选易感基因。这种变异还可能增加肿瘤远处转移的风险。本课题第二部分研究糖尿病易感基因之一TCF7L2与汉族女性乳腺癌的发病风险。结果表明TCF7L2基因rs7903146、rs12255372多态性与中国汉族女性乳腺癌的发病风险无关。多项研究显示，胰岛素样生长因子2mRNA结合蛋白2（insulin-like growth factor2binding proteins2，IGF2BP2）基因2号内含子上的SNPs rsl470579和rs4402960对2型糖尿病的发展有中度危险性，并在多项人群的重复试验和meta分析中得到证实。但尚未见IGF2BP2基因多态性与乳腺癌关系的报道，因此本课题第三部分研究了IGF2BP2基因rs4402960多态性与中国汉族女性乳腺癌患病风险的关系，结果显示IGF2BP2基因rs4402960多态性可增加中国汉族女性乳腺癌的患病风险。
主要研究内容和结果如下：
第一部分乳腺癌合并2型糖尿病的临床病理特征及预后分析
目的：探讨2型糖尿病与乳腺癌临床病理特征及预后的关系。
方法：随机选取2011年1月-2012年1月于河北医科大学第四医院住院的女性乳腺癌患者240例。将研究对象按是否合并有2型糖尿病分为乳腺癌合并糖尿病组及乳腺癌非糖尿病组,乳腺癌合并糖尿病组包括80例患者,乳腺癌非糖尿病组纳入160例患者。均经外科手术治疗和术后病理切片证实为原发性乳腺癌。查阅病历资料，包括患者姓名、年龄、身高、体重、血糖、初潮年龄、产次、绝经状态、肿瘤大小、淋巴结转移情况、主要免疫组化指标（ER、PR、HER-2及Ki-67）、肿瘤组织学分级、临床分期及分子分型等。采用SPSS13.0统计软件对数据进行分析。计量资料以均数标准差(x s)表示,采用两样本均数比较的t检验;计数资料采用四格表资料的χ2检验。P0.05为差异有统计学意义。
结果：1.乳腺癌合并2型糖尿病组年龄明显高于乳腺癌非糖尿病组，差异有统计学意义，但两组间的BMI无统计学差异。
2.乳腺癌合并2型糖尿病组血糖值明显高于乳腺癌非糖尿病组，差异有统计学意义。
3.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组在初潮年龄、产次方面比较无统计学差异，乳腺癌合并2型糖尿病组绝经后患者明显多于乳腺癌非糖尿病组，两组间比较有统计学差异。
4.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组的肿瘤大小、淋巴结转移情况、ER、PR、HER-2及Ki-67状态等比较均无统计学差异。
5.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组的临床分期、组织学分级及分子分型比较有统计学差异，乳腺癌合并2型糖尿病组的临床分期、组织学分级及Basal-like型者均高于乳腺癌非糖尿病组，差异有统计学意义。乳腺癌合并2型糖尿病组较乳腺癌非糖尿病组肿瘤临床分期更晚，组织学分级更高，Basal-like型者更常见，预后较差。
结论：1.乳腺癌合并2型糖尿病多见于年龄较大者及绝经后者，对年龄较大的尤其是绝经后的2型糖尿病患者应定期进行乳腺超声及钼靶等检查。
2.乳腺癌合并2糖尿病组与乳腺癌非糖尿病组相比，BMI、初潮年龄、产次、肿瘤大小、淋巴结转移情况、ER、PR、HER-2及Ki-67状态等均无明显统计学差异。但乳腺癌合并2型糖尿病患者的临床分期较晚，组织学分级较高，Basal-like型者更常见，预后较差。2型糖尿病是乳腺癌患者预后不良的危险因素。第二部分TCF7L2基因多态性与汉族女性乳腺癌风险的相关性研究
目的：探讨2型糖尿病的易感基因之一核转录因子7类似物2（TCF7L2）的多态性与汉族女性乳腺癌发病风险的关系。
方法：采用病例对照研究，抽取河北医科大学第四医院住院的汉族女性乳腺癌患者及来自白求恩国际和平医院同期健康体检汉族女性的外周血，提取基因组DNA，采用聚合酶链反应-连接酶检测反应(polymerasechain reaction-ligase detection reaction，PCR-LDR)分型方法检测TCF7L2基因rs7903146、rs12255372多态性，比较基因型频率分布和患病风险及临床病理特征的关系。采用SPSS13.0软件包进行统计学分析。采用χ2检验对正常对照组的基因型分布频率进行Hardy-Weinberg平衡检验。病例组和对照组的年龄、BMI差异采用t检验。采用χ2检验比较TCF7L2各基因型在病例与对照组之间分布的差异。采用Logistic回归计算比值比(Odds Ratio, OR)及其95%可信区间(Confidence Interval, CI)评估TCF7L2单核苷酸多态性与乳腺癌患病风险及临床病理参数的关系,并以年龄、BMI进行校正。P0.05表示差异有统计学意义。
结果：1.乳腺癌组患者平均年龄为49.1±9.6岁，正常对照组患者年龄为48.1±9.9岁，两组间差异无统计学意义。乳腺癌组患者BMI为25.5±3.6kg/m2，正常对照组患者BMI为25.4±3.5kg/m2，两组间差异有统计学意义（P0.001）。
2.乳腺癌组和对照组TCF7L2基因rs7903146C/T的基因型频率分布情况：两组人群均未检测出TT基因型,乳腺癌组CC、CT两种基因型频率分别为92.7％和7.3％，与对照组各基因型频率89.3%、10.7%相比，差异无显著性(χ2=3.369P=0.066)。与CC基因型比较，携带CT基因型未显著改变乳腺癌的发病风险(OR=1.522，95%CI=0.97-2.389)。乳腺癌组和对照组TCF7L2基因rs12255372G/T的基因型频率分布情况：乳腺癌组GG、GT两种基因型频率分别为98.2％和1.8％，与对照组各基因型频率97.7%、2.3%相比，差异无显著性(χ2=0.312P=0.577)。与GG基因型比较，携带GT基因型未显著改变乳腺癌的发病风险(OR=1.295，95%CI=0.512-3.217)。
3.按诊断时年龄进行分层分析发现,诊断时年龄<50岁的乳腺癌患者共301例，其中rs7903146CT型有14例，突变率为4.7%；rs12255372GT型有3例，突变率为1%。诊断时年龄≥50岁的乳腺癌患者共263例，rs7903146CT型有27例，突变率为9.3%；rs12255372GT型有7例，突变率为2.7%。诊断时年龄≥50岁的乳腺癌患者rs7903146位点突变率明显高于诊断时年龄<50岁者，两组患者间基因型分布有统计学差异（P0.05），OR值为2.345(95%CI=1.202-4.575)；诊断时年龄≥50岁的乳腺癌患者rs12255372位点突变率与诊断时年龄50岁者相比无统计学差异。
4.按绝经状态分层分析发现，绝经前的乳腺癌患者共258例，其中rs7903146CT型有12例，突变率为4.7%；绝经后的乳腺癌患者共278例，其中CT型有26例，突变率为9.4%。两组患者间基因型分布有统计学差异（P0.05）。绝经后组患者发生基因突变的可能性明显高于绝经前组，OR值为2.115(95%CI=1.044-4.286);绝经前患者中rs12255372GT型有1例，突变率为0.4%；绝经后的乳腺癌患者中rs12255372GT型有7例，突变率为2.5%。两组患者间基因型分布无统计学差异（P>0.05）。
5.按ER状态分层分析显示，ER阴性的乳腺癌患者共179例，其中rs7903146CT型有10例，突变率为5.6%；rs12255372GT型有2例，突变率为1.1%。ER阳性的乳腺癌患者共345例，其中CT型有29例，突变率为8.4%；rs12255372GT型有8例，突变率为2.3%。两组患者间基因型分布均无统计学差异（P>0.05）。
6.按PR状态分层分析发现，PR阴性的乳腺癌患者共227例，其中rs7903146CT型有17例，突变率为7.5%；GT型有5例，突变率为2.2%。PR阳性的乳腺癌患者共296例，其中rs7903146CT型有22例，突变率为7.4%；rs12255372GT型有5例，突变率为1.7%。两组患者间基因型分布均无统计学差异（P>0.05）。
7.按HER-2状态分层分析发现，HER-2阴性的乳腺癌患者共396例，其中rs7903146CT型有27例，突变率为6.8%；rs12255372GT型有8例，突变率为2%。HER-2阳性的乳腺癌患者共123例，其中rs7903146GT型有11例，突变率为8.9%；rs12255372GT型有2例，突变率为1.6%。两组患者间基因型分布均无统计学差异（P>0.05）。
8.按P53状态分层分析显示，P53阴性的乳腺癌患者共118例，其中rs7903146CT型有9例，突变率为7.6%；rs12255372GT型有3例，突变率为2.5%。P53阳性的乳腺癌患者共327例，其中rs7903146CT型有26例，突变率为8%；rs12255372GT型有4例，突变率为1.2%。两组患者间基因型分布均无统计学差异（P>0.05）。
9.按Ki-67状态分层分析显示，Ki-67阴性的乳腺癌患者共84例，其中rs7903146CT型有5例，突变率为6%；rs12255372GT型有1例，突变率为1.2%。Ki-67阳性的乳腺癌患者共379例，其中rs7903146CT型有30例，突变率为7.9%；rs12255372GT型有6例，突变率为1.6%。两组患者间基因型分布无统计学差异（P>0.05）。
10.按有无淋巴结转移分层分析显示，无淋巴结转移的乳腺癌患者共251例，其中rs7903146CT型有16例，突变率为6.4%；rs12255372GT型有5例，突变率为2%。有淋巴结转移的乳腺癌患者共255例，其中rs7903146CT型有20例，突变率为7.8%；rs12255372GT型有3例，突变率为1.2%。两组患者间基因型分布均无统计学差异（P>0.05）。
11.按肿瘤大小分层分析显示，肿瘤直径≤2cm的乳腺癌患者共248例，其中rs7903146CT型有14例，突变率为5.6%；rs12255372GT型有1例，突变率为0.4%。肿瘤直径>2cm的乳腺癌患者共234例，其中rs7903146CT型有20例，突变率为8.5%；rs12255372GT型有6例，突变率为2.5%。两组患者间基因型分布均无统计学差异（P>0.05）。
12.按组织学分级分层分析发现，组织学分级为Ⅰ-Ⅱ级的乳腺癌患者共349例，其中rs7903146CT型有29例，突变率为8.3%；rs12255372GT型有7例，突变率为7%。组织学分级为Ⅲ级的乳腺癌患者共46例，其中rs7903146CT型有1例，突变率为2.2%；rs12255372GT型有0例，突变率为0%。两组患者间基因型分布均无统计学差异（P>0.05）。
13.按肿瘤临床分期分层分析显示，临床分期为Ⅰ期的乳腺癌患者共155例，其中rs7903146CT型有9例，突变率为5.8%；rs12255372GT型有2例，突变率为1.3%。临床分期为Ⅱ期的乳腺癌患者共215例，其中rs7903146CT型有19例，突变率为8.8%；rs12255372GT型有5例，突变率为2.3%。临床分期为Ⅲ期的乳腺癌患者共156例，其中rs7903146CT型有10例，突变率为6.4%；rs12255372GT型有2例，突变率为1.3%。临床分期为Ⅳ期的乳腺癌患者共38例，其中rs7903146CT型有3例，突变率为7.9%；rs12255372GT型有1例，突变率为2.6%。两组患者间基因型分布无统计学差异（P>0.05）。
14.按分子分型分层分析显示，Luminal A型的乳腺癌患者共74例，其中rs7903146CT型有5例，突变率为6.8%；rs12255372GT型有1例，突变率为1.4%。Luminal B型的乳腺癌患者共254例，其中rs7903146CT型有24例，突变率为9.4%；rs12255372GT型有6例，突变率为2.4%。ERBB2+型的乳腺癌患者共66例，其中rs7903146CT型有2例，突变率为3%；rs12255372GT型有0例，突变率为0%。Basal-like型的乳腺癌患者共93例，其中rs7903146CT型有6例，突变率为6.5%；rs12255372GT型有2例，突变率为2.2%。两组患者间基因型分布无统计学差异（P>0.05）。
结论：1.乳腺癌组患者与正常对照组间年龄无统计学差异，乳腺癌组患者的BMI高于正常对照组，提示BMI是乳腺癌患病的危险因子，正常人群应该注意控制饮食、加强锻炼以减轻BMI，从而降低患乳腺癌的风险。
2. TCF7L2基因多态位点rs7903146突变在绝经后患者及诊断时年龄≥50岁者明显高于绝经前者及诊断时年龄<50岁者，但TCF7L2基因多态位点rs12255372基因突变与绝经状态及诊断时年龄无关。
3. TCF7L2基因多态位点rs7903146及rs12255372基因多态性与乳腺癌的发病风险无关，且与淋巴结转移情况、雌孕激素受体、HER-2受体状态、P53、Ki-67状态、肿瘤大小、组织学分级、肿瘤分期及分子分型均无明显相关性。第三部分IGF2BP2基因多态性与汉族女性乳腺癌发病风险的关联研究
目的：探讨2型糖尿病的易感基因之一胰岛素样生长因子2mRNA结合蛋白2（IGF2BP2）的多态性与乳腺癌发病风险的关系。
方法：采用病例对照研究，抽取河北医科大学第四医院住院的汉族女性乳腺癌患者及来自白求恩国际和平医院同期健康体检汉族女性的外周血，提取基因组DNA，采用聚合酶链反应-连接酶检测反应(polymerasechain reaction-ligase detection reaction，PCR-LDR)分型方法检测IGF2BP2基因rs4402960多态性，比较基因型频率分布和患病风险及临床病理特征的关系。采用SPSS13.0软件包进行统计学分析。采用χ2检验对对照组的基因型分布频率进行Hardy-Weinberg平衡检验。病例组和对照组的年龄、BMI差异采用t检验。采用χ2检验比较IGF2BP2各基因型在病例与对照组之间分布的差异。采用Logistic回归计算比值比(Odds Ratio,OR)及其95%可信区间(Confidence Interval, CI)评估IGF2BP2单核苷酸多态性与乳腺癌患病风险及临床病理参数的关系,并以年龄、BMI进行校正。所有统计检验均为双侧概率检验, P0.05表示差异有统计学意义。
结果：1.乳腺癌组患者平均年龄为49.1±9.6岁，正常对照组患者年龄为48.1±9.9岁，两组间差异无统计学意义。乳腺癌组患者BMI为25.5±3.6kg/m2，正常对照组患者BMI为25.4±3.5kg/m2，两组间差异有统计学意义（P0.001）。
2.乳腺癌组和对照组IGF2BP2基因rs4402960G/T的基因型频率分布情况：病例组的GT(43.3%)、TT(6.2%)频率、T基因型（GT+TT）（49.5%）及T等位基因（27.8%）明显高于对照组的GT(36.5%)、TT(3.6%)频率、T基因型（GT+TT）（40.1%）及T等位基因（21.8%）。 GT（ORadj=1.442;95%CI,1.097-1.895）、TT（ORadj=2.0;95%CI,1.041-3.843）基因型，T基因型携带者（GT+TT）（ORadj=1.494;95%CI,1.146-1.947）及T等位基因（ORadj=1.391;95%CI,1.120-1.727）均明显增加乳腺癌的发病风险。
3.按诊断时年龄进行分层分析发现,诊断时年龄50岁的乳腺癌患者共301例，其中GG型有151例(50.2%)，GT型有134例(44.5%)， TT型有16例（5.3%），T基因型携带者为150例（49.8%）；诊断时年龄≥50岁的乳腺癌患者共263例，其中GG型有134例(51%)，GT型有110例(41.8%)，TT型有19例（7.2%）T基因型携带者为129例（49%）。两组患者间基因型分布无统计学差异（P>0.05）。
4.按绝经状态分层分析发现，绝经前的乳腺癌患者共258例，其中GG型有134例（51.9%），GT型有112例（43.4%），TT型有12例（4.7%），T基因型携带者为124例（48.1%）；绝经后的乳腺癌患者共278例，其中GG型有136例（48.9%），GT型有121例（43.5%），TT型有21例（7.6%），T基因型携带者为142例（51.1%）。两组患者间基因型分布无统计学差异（P>0.05）。
5.按ER状态分层分析显示，ER阴性的乳腺癌患者共179例，其中GG型有97例（54.2%），GT型有71例（39.7%），TT型有11例（6.1%），T基因型携带者为82例（45.8%）；ER阳性的乳腺癌患者共345例，其中GG型有175例（50.7%），GT型有150例（43.5%），TT型有20例（5.8%），T基因型携带者为170例（49.3%）。两组患者间基因型分布无统计学差异（P>0.05）。
6.按PR状态分层分析发现，PR阴性的乳腺癌患者共227例，其中GG型有121例(53.3%)，GT型有92例(40.5%)，TT型有14例（6.2%），T基因型携带者为106例（46.7%）；PR阳性的乳腺癌患者共296例，GG型有151例(51%)，GT型有128例(43.2%)，TT型有17例（5.7%），T基因型携带者为145例（49%）。两组患者间基因型分布无统计学差异（P>0.05）。
7.按HER-2状态分层分析发现，HER-2阴性的乳腺癌患者共396例，GG型有209例(52.8%)，GT型有161例(40.7%)，TT型有26例（6.6%），T基因型携带者为187例（47.2%）；HER-2阳性的乳腺癌患者共123例，GG型有60例(48.8%)，GT型有59例(48%)，TT型有4例（3.3%），T基因型携带者为63例（51.2%）。两组患者间基因型分布无统计学差异（P>0.05）。
8.按P53状态分层分析显示，P53阴性的乳腺癌患者共118例，其中GG型有65例(55.1%)，GT型有48例(40.7%)，TT型有5例（4.2%），T基因型携带者为53例（44.9%）；P53阳性的乳腺癌患者共327例，GG型有168例(51.4%)，GT型有139例(42.5%)，TT型有20例（6.1%），T基因型携带者为159例（48.6%）。两组患者间基因型分布无统计学差异（P>0.05）。
9.按Ki-67状态分层分析显示，Ki-67阴性的乳腺癌患者共84例，GG型有43例(51.2%)，GT型有39例(46.4%)，TT型有2例（2.4%），T基因型携带者为41例（48.8%）；Ki-67阳性的乳腺癌患者共379例，GG型有200例(52.8%)，GT型有155例(40.9%)，TT型有24例（6.3%），T基因型携带者为179例（47.2%）。两组患者间基因型分布无统计学差异（P>0.05）。
10.按有无淋巴结转移分层分析显示，无淋巴结转移的乳腺癌患者共251例，GG型有128例(51%)，GT型有106例(42.2%)，TT型有17例（6.8%），T基因型携带者为123例（49%）；有淋巴结转移的乳腺癌患者共255例，GG型有131例(51.4%)，GT型有109例(42.7%)，TT型有15例（5.9%），T基因型携带者为124例（48.6%）。两组患者间基因型分布无统计学差异（P>0.05）。
11.按肿瘤大小分层分析显示，肿瘤直径≤2cm的乳腺癌患者共248例，GG型有133例(53.6%)，GT型有100例(40.3%)，TT型有15例（6%），T基因型携带者为115例（46.4%）；肿瘤直径>2cm的乳腺癌患者共234例，GG型有109例(46.6%)，GT型有111例(47.4%)，TT型有14例（6%），T基因型携带者为125例（53.4%）。两组患者间基因型分布无统计学差异（P>0.05）。
12.按组织学分级分层分析发现，组织学分级为Ⅰ-Ⅱ级的乳腺癌患者共349例，GG型有191例(54.7%)，GT型有141例(40.4%)，TT型有17例（4.9%），T基因型携带者为158例（45.3%）；组织学分级为Ⅲ级的乳腺癌患者共46例，GG型有23例(50%)，GT型有18例(39.1%)，TT型有5例（10.9%），T基因型携带者为23例（50%）。两组患者间基因型分布无统计学差异（P>0.05）。
13.按肿瘤临床分期分层分析显示，临床分期为Ⅰ期的乳腺癌患者共155例，其中GG型有84例(54.2%)，GT型有60例(38.7%)，TT型有11例（7.1%），T基因型携带者为71例（45.8%）；临床分期为Ⅱ期的乳腺癌患者共215例，GG型有117例(54.4%)，GT型有88例(40.9%)，TT型有10例（4.7%），T基因型携带者为98例（45.6%）；临床分期为Ⅲ期的乳腺癌患者共156例，GG型有69例(44.2%)，GT型有76例(48.7%)，TT型有11例（7.1%），T基因型携带者为87例（55.8%）；临床分期为Ⅳ期的乳腺癌患者共38例，GG型有15例(39.5%)，GT型有20例(52.6%)，TT型有3例（7.9%），T基因型携带者为23例（60.5%）。两组患者间基因型分布无统计学差异（P>0.05）。
14.按分子分型分层分析显示，Luminal A型的乳腺癌患者共74例，其中GG型有39例(52.7%)，GT型有33例(44.6%)，TT型有2例（2.7%），T基因型携带者为35例（47.3%）；Luminal B型的乳腺癌患者共254例，GG型有130例(51.2%)，GT型有108例(42.5%)，TT型有16例（6.3%），T基因型携带者为124例（48.8%）；ERBB2+型的乳腺癌患者共66例，GG型有34例(51.5%)，GT型有30例(45.5%)，TT型有2例（3%），T基因型携带者为32例（48.5%）。Basal-like型的乳腺癌患者共93例，GG型有52例(55.9%)，GT型有35例(37.6%)，TT型有6例（6.5%），T基因型携带者为41例（44.1%）；两组患者间基因型分布无统计学差异（P>0.05）。
结论：1.乳腺癌组患者与正常对照组间年龄比较无统计学差异，乳腺癌组患者的BMI高于正常对照组，提示BMI是乳腺癌患病的危险因子，正常人群应该注意控制饮食、加强锻炼以减轻BMI，从而降低患乳腺癌的风险。
2. IGF2BP2基因多态位点rs4402960基因多态性与乳腺癌的发病风险有关，经校正年龄及BMI后， T基因型携带者（GT+TT）（ORadj=1.494;95%CI,1.146-1.947）及T等位基因（ORadj=1.391;95%CI,1.120-1.727）均明显增加乳腺癌的发病风险。但与诊断时年龄、绝经状态、淋巴结转移情况、雌孕激素受体、HER-2受体状态、P53、Ki-67状态、肿瘤大小、组织学分级及肿瘤临床分期均无明显相关性。
Breast cancer is one of the most common malignant tumors in females.With an annual incidence rate increased by more than3%in the past few years,it is the number one cause in morbidity among all the malignant tumor typesin Chinese females. Diabetes, often referred to as diabetes mellitus, is a groupof diseases characterized by glycometabolism disorders and caused by geneticas well as environmental reasons. Insulin deficiency and dysfunction may acttogether or independently to induce metabolic disorders of carbohydrates,lipids, proteins, water and electrolytes. There have recently been drasticincreases in the incidence rate of diabetes in a worldwide range, and China isbecoming one of the countries with the highest diabetes morbidity, where thediabetes population is expected to exceed that of India and become No.1in2020. There is Meta analysis that shows the corresponding risk of breastcancer in patients diagnosed with type2diabetes is1.2-1.5fold of that of thenormal people. In the first part of this research, to investigate the effects oftype2diabetes mellitus on the clinico-pathological characteristics andprognosis of breast cancer, we retrospectively analyzed the medical records of80breast cancer patients with type2diabetes and160non-diabetic breastcancer patients.
More and more previous investigations indicate that there might becomplicated correlations between type2diabetes and breast cancers, but theunderlying mechanism remains to be explored. Gene mutations are believed tobe correlated with both of the above two diseases, and similar gene mutationsmight partially explain the correlation between diabetes and breast cancer. Thetranscription factor7-like2(TCF7L2) gene is located on the chromosome10q25.2, which was also known previously as TCF-4. The gene encodes ahigh mobility group box-containing transcription factor which is involved in Wnt/β-catenin signaling pathway. The analysis of multiple whole genomeassociation illustrates that TCF7L2is one of the susceptibility genes for type2diabetes. Barbara et al. investigated the effect of the TCF7L2rs12255372variant on familial breast cancer (BC) risk by means of TaqMan allelicdiscrimination. Their results suggest a possible influence of TCF7L2rs12255372on the risk of familial BC. Genotyping of TCF7L2polymorphisms was performed on387breast cancer patients and252healthywomen who had no history of any malignancy using polymerase chainreaction–restriction fragment length polymorphism (PCR–RFLP) method in ahospital-based Malaysian population by Naidu et al. The allele frequency ofrs7903146(T) polymorphism was significantly higher in the cancer patientsthan normal individuals. No significant association was demonstrated betweenCT and TT genotype and breast cancer risk. However, women who werecarriers of T allele or T allele genotype showed significant increased risk ofbreast cancer. The rs7903146(T) allele genotype was significantly associatedwith nodal involvement but rs12255372(T) allele genotype was not associatedwith the clinico-pathologic characteristics. In conclusion, rs7903146(T)variant may elevate the risk of breast cancer, thus could be a potentialcandidate for breast cancer susceptibility. The variant may also increase themetastatic potential of the tumor. The second part of this study is to investigatethe association of TCF7L2and the risk of breast cancer. The results showedthat the gene TCF7L2rs7903146, rs12255372polymorphisms were notassociated with the risk of breast cancer in Chinese Han. Many studies haveshown that the SNPs rs1470579and rs4402960in the second intron ofIGF2BP2gene is of medium risk in the development of type2diabetesmellitus, and such results have been proven by investigations and Metaanalysis repeated in various populations. However, there have not been anyreports about the correlations between IGF2BP2gene polymorphism andbreast cancer, and therefore we investigated the polymorphism of IGF2BP2gene, rs4402960, and its correlation to the risk of breast cancer in Chinesefemales of Han nationality. The research contents and results are as follows: Part I The clinico-pathologic characteristics and prognosis in breastcancer patients with type2diabetes
Objective: To investigate the association of type2diabetes mellitus onthe clinico-pathologic characteristics and prognosis of breast cancer.
Methods: A case-control study, which includes240female breast cancerPatients, who were in-hospital in the fourth affiliated hospital of HebeiMedical University from January2011to January2012. The Patients weredivided into two groups according to incidence of type2diabetes. Breastcancer and diabetes group included80patients, non-diabetic group included160patients. They all had been operated and their pathology slices werediagnosed primary breast. We reviewed patients’ medical records, includingpatient name, age, height, weight, blood glucose, age at menarche, parity,menopausal status, tumor size, lymph node metastasis, the major indexesimmunohistochemistry (ER, PR, HER-2, Ki-67), tumor histological grade,clinical stage and molecular typing, etc. SPSS13.0statistical software wasused to do the statistics analysis. Measurement data were expressed as mean standard deviation, and compared using t-test; count data tables were analyzedby the x2test. P <0.05was considered significantly difference.
Results:1. Breast cancer patients with type2diabetes were older thanthose in non-diabetic group, the difference was statistically significant, butthere was no significant difference in BMI between the two groups.
2. In breast cancer patients with type2diabetes, blood glucose weresignificantly higher than the non-diabetic patients, the difference wasstatistically significant.
3. There were no significant difference in age at menarche and paritybetween Breast cancer patients with type2diabetes mellitus and non-diabeticpatients, postmenopausal patients in the group of breast cancer patients withtype2diabetes have significantly more than those in non-diabetic patientsgroup, there were significant differences between the two groups.
4. There was no significant difference in the distribution of tumor size,lymph node metastasis, ER, PR, HER-2and Ki-67status between group of breast cancer patients with type2diabetes and non-diabetic group.
5. Significant differences in the distribution of clinical stage, histologicalgrade and molecular typing between group of breast cancer patients with type2diabetes and non-diabetic group, the higher clinical stage, histological gradeand Basal-like type were found in group of breast cancer patients with type2diabetes than in non-diabetic group. The difference was statisticallysignificant.
Conclusions:1. Breast cancer with type2diabetes is more common inpatients with older age and post menopause. Elder type2diabetes patientsespecially for postmenopausal should be regularly examined by breastultrasound and mammography.
2. There was no significant difference in the distribution of BMI, age atmenarche, parity, tumor size, lymph node metastasis, ER, PR, HER-2andKi-67status between group of breast cancer patients with type2diabetes andnon-diabetic group. The higher clinical stage, histological grade and Basal-liketype were found in group of breast cancer patients with type2diabetes than innon-diabetic group. Type2diabetes is the risk factor of breast cancer withpoor prognosis. Female breast cancer patients with type2diabetes have laterclinical stage and poor prognosis.Part II The association of TCF7L2gene polymorphism with breast cancerrisk in Chinese Han female
Objective: To investigate the relationship of nuclear transcription factor7like2(TCF7L2) gene which is one of diabetes susceptibility genespolymorphism and risk of breast cancer.
Methods: In this case-control study, peripheral blood was extracted fromwomen with breast cancer hospitalized in The Fourth Hospital of HebeiMedical University and from the same period healthy volunteers in BethuneInternational Peace Hospital. Genomic DNA was extracted from peripheralblood. The TCF7L2rs7903146, rs12255372polymorphism were detected byPolymerase chain reaction-ligase detection reaction (PCR-LDR) method, andwe analyzed the relationships of genotype frequency distributions and the risk and clinic-pathological features of breast cancer. Statistical analysis wasperformed using SPSS13.0software package. Hardy–Weinberg analysis wasperformed by comparing the genotype frequencies in the control group usingthe chi-square test. The age and BMI difference of two groups was analyzedby the t-test. Comparison of the TCF7L2genotype and allele distribution inpatients and healthy controls was performed by Chi-square test. The odds ratio(OR) and95%confidence Interval (CI) were calculated using anunconditional logistic regression model. We assessed the relationship betweenTCF7L2single nucleotide polymorphisms and the risk of breast cancer andclinic-pathological parameters adjusted by age and BMI. P <0.05wasconsidered significantly difference.
Results:1.The average age of breast cancer patients was49.1±9.6yearsand48.1±9.9years in the control group of patients. The difference was notstatistically significant. The body mass index was25.5±3.6kg/m2in breastcancer patients and25.4±3.5kg/m2in normal control group, the differencebetween the two groups was statistically significant (P <0.001).
2. Two groups were not detected TT genotype.The genotype frequenciesof the TCF7L2rs7903146CC and CT in patients with breast cancer andcontrols were92.7％,7.3％and89.3%,10.7%respectively. No statisticallysignificant difference in the TCF7L2genotype distribution was demonstratedbetween cases and controls (χ2=3.369P=0.066). Compared to the CCgenotype, the CT genotype did not increase the risk of developing breastcancer, the odds ratio were1.522(95%CI=0.97-2.389). The allele frequenciesof the TCF7L2rs12255372CC and CT in patients with breast cancer andcontrols were98.2％,1.8％and97.7%,2.3%respectively. No statisticallysignificant difference in the TCF7L2allele distribution was demonstratedbetween cases and controls (χ2=0.312P=0.577). Compared to the CCgenotype, the CT genotype did not increase the risk of developing breastcancer, the odds ratio were1.295(95%CI=0.512-3.217).
3. Stratified analysis by age at diagnosis found that the total number ofage at diagnosis <50years was301in breast cancer patients, of which there were14cases of rs7903146CT type. The mutation rate was4.7%. There were3cases of rs12255372GT type in301cases. The mutation rate was1%.Thetotal number of age at diagnosis≥50years was263in breast cancer patients,of which there were27cases of rs7903146CT type. The mutation rate was9.3%. There were7cases of rs12255372GT type in263cases. The mutationrate was2.7%. The mutation rate of TCF7L2rs7903146was significantlyhigher in breast cancer patients whose age at diagnosis≥50years than thoseage at diagnosis <50years. The difference of genotype between the twogroups was statistically significant (P <0.05), the odds ratio were2.345(95%CI=1.202-4.575). The difference of rs12255372mutation rate between twogroups was not statistically significant (P>0.05).
4. Stratified analysis by menopausal status found that the total number ofpre-menopausal breast cancer patients was258, of which there were12casesof rs7903146CT type. The mutation rate was4.7%. The total number ofpost-menopausal breast cancer patients was278, of which there are26casesof CT type. The difference of genotype between the two groups wasstatistically significant (P<0.05). The rs7903146mutation rate inpostmenopausal breast cancer patients than those in pre-menopausal breastcancer patients, the odds ratio were2.115(95%CI=1.044-4.286). There were12cases of rs7903146CT type. The mutation rate was4.7%. There were onecases of GT type in pre-menopausal breast cancer patients. The mutation ratewas0.4%. There were seven cases of GT type in post-menopausal breastcancer patients. The mutation rate was2.5%. The difference in genotypedistribution between the two groups was not statistically significant (P>0.05).
5. Stratified analysis by ER status showed that the total number of ERnegative breast cancer patients was179, of which there were12cases ofrs7903146CT type. The mutation rate was5.6%. There were two cases ofrs12255372GT type in179cases. The mutation rate was1.1%.The totalnumber of ER positive breast cancer patients was345, of which there are29cases of rs7903146CT type. The mutation rate was8.4%. There were eightcases of rs12255372GT type in345cases. The mutation rate was2.3%. The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
6. Stratified analysis by PR status showed that the total number of PRnegative breast cancer patients was227, of which there were17cases ofrs7903146CT type. The mutation rate was7.5%. There were five cases ofrs12255372GT type in227cases. The mutation rate was2.2%.The totalnumber of PR positive breast cancer patients was296, of which there are22cases of rs7903146CT type. The mutation rate was7.4%. There were fivecases of rs12255372GT type in296cases. The mutation rate was1.7%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
7. Stratified analysis by HER-2status showed that the total number ofHER-2negative breast cancer patients was396, of which there were27casesof rs7903146CT type. The mutation rate was6.8%. There were eight cases ofrs12255372GT type in227cases. The mutation rate was2%.The total numberof HER-2positive breast cancer patients was123of which there are11casesof rs7903146CT type. The mutation rate was8.9%. There were two cases ofrs12255372GT type in123cases. The mutation rate was1.6%. The differencein genotype distribution between the two groups was not statisticallysignificant (P>0.05).
8. Stratified analysis by P53status showed that the total number of P53negative breast cancer patients was118, of which there were nine cases ofrs7903146CT type. The mutation rate was7.6%. There were three cases ofrs12255372GT type in118cases. The mutation rate was2.5%.The totalnumber of P53positive breast cancer patients was327, of which there are26cases of rs7903146CT type. The mutation rate was8%. There were four casesof rs12255372GT type in327cases. The mutation rate was1.2%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
9. Stratified analysis by Ki-67status showed that the total number ofKi-67negative breast cancer patients was84, of which there were five cases of rs7903146CT type. The mutation rate was6%. There were one cases ofrs12255372GT type in84cases. The mutation rate was1.2%.The totalnumber of Ki-67positive breast cancer patients was463, of which there are30cases of rs7903146CT type. The mutation rate was7.9%. There were sixcases of rs12255372GT type in379cases. The mutation rate was1.6%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
10. Stratified analysis by lymph node metastasis showed that the totalnumber of breast cancer patients without lymph node metastasis was251, ofwhich there were16cases of rs7903146CT type. The mutation rate was6.4%.There were five cases of rs12255372GT type in251cases. The mutation ratewas2%.The total number of breast cancer patients with lymph nodemetastasis was255, of which there are20cases of rs7903146CT type. Themutation rate was7.8%. There were three cases of rs12255372GT type in255cases. The mutation rate was1.2%. The difference in genotype distributionbetween the two groups was not statistically significant (P>0.05).
11. Stratified analysis by tumor size showed that the total number ofbreast cancer patients whose tumor diameter≤2cm was248, of which therewere14cases of rs7903146CT type. The mutation rate was5.6%. There were1cases of rs12255372GT type in248cases. The mutation rate was0.4%.Thetotal number of breast cancer patients whose tumor diameter>2cm was234,of which there are20cases of rs7903146CT type. The mutation rate was8.5%. There were six cases of rs12255372GT type in234cases. The mutationrate was2.5%. The difference in genotype distribution between the two groupswas not statistically significant (P>0.05).
12. Stratified analysis by histological grade showed that the total numberof histological grade of Ⅰ-Ⅱ breast cancer patients was349, of which therewere29cases of rs7903146CT type. The mutation rate was8.3%. There wereseven cases of rs12255372GT type in349cases. The mutation rate was7%.The total number of histological grade of Ⅲ breast cancer patients was46, of which there are1cases of rs7903146CT type. The mutation rate was 2.2%. There were zero cases of rs12255372GT type in234cases. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
13. Stratified analysis by tumor clinical staging showed that the totalnumber of stage Ⅰ breast cancer patients was155, of which there were ninecases of rs7903146CT type. The mutation rate was5.8%. There were twocases of rs12255372GT type in155cases. The mutation rate was1.3%.Thetotal number of stage Ⅱ breast cancer patients was215, of which there are19cases of rs7903146CT type. The mutation rate was8.8%. There were fivecases of rs12255372GT type in215cases. The mutation rate was2.3%. Thetotal number of stage Ⅲ breast cancer patients was156, of which there are10cases of rs7903146CT type. The mutation rate was6.4%. There were twocases of rs12255372GT type in156cases. The mutation rate was1.3%. Thetotal number of stage Ⅳbreast cancer patients was38, of which there arethree cases of rs7903146CT type. The mutation rate was7.9%. There wereone cases of rs12255372GT type in38cases. The mutation rate was2.6%.The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
14. Stratified analysis by molecular typing showed that the total numberof Luminal A type breast cancer patients was74, of which there were fivecases of rs7903146CT type. The mutation rate was6.8%. There were onecases of rs12255372GT type in74cases. The mutation rate was1.4%.Thetotal number of Luminal B type breast cancer patients was254, of which thereare24cases of rs7903146CT type. The mutation rate was9.4%. There weresix cases of rs12255372GT type in254cases. The mutation rate was2.4%.The total number of ERBB2+type breast cancer patients was66, of whichthere are two cases of rs7903146CT type. The mutation rate was3%. Therewere zero cases of rs12255372GT type in66cases. The mutation rate was0%.The total number of Basal-like type breast cancer patients was93, of whichthere are six cases of rs7903146CT type. The mutation rate was6.5%. Therewere two cases of rs12255372GT type in38cases. The mutation rate was 2.2%. The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
Conclusions:1.There was no significant difference between the age ofbreast cancer patients and normal control cases. BMI of breast cancer patientswas higher than which of the control cases, suggesting that BMI is a riskfactor for breast cancer disease. Normal people should pay attention to dietand exercise to decline BMI, thereby reducing the risk of breast cancer.
2. The mutation of TCF7L2gene rs7903146polymorphisms in thepost-menopausal and age at diagnosis≥50years patients was significantlyhigher than the pre-menopause and age at diagnosis <50years patients. Themutation of TCF7L2gene rs12255372polymorphisms was not associatedwith menopausal status and age at diagnosis.
3. There was no relationship between the TCF7L2gene rs7903146andrs12255372polymorphisms and risk of breast cancer, lymph node metastasis,estrogen receptor, progesterone receptor, HER-2receptor status, P53, Ki-67status, tumor size, histological grade, tumor stage and molecular typing.Part III The association of IGF2BP2gene polymorphism with breastcancer risk in Chinese Han female
Objective: To investigate the relationship of Insulin-like growth factor2mRNA binding protein2(IGF2BP2) which is one of the diabetessusceptibility genes polymorphism and risk of breast cancer.
Methods: In this case-control study, peripheral blood was extracted fromwomen with breast cancer hospitalized in The Fourth Hospital of HebeiMedical University and from the same period healthy volunteers in BethuneInternational Peace Hospital. Genomic DNA was extracted from peripheralblood. The IGF2BP2rs4402960polymorphism was detected by Polymerasechain reaction-ligase detection reaction (PCR-LDR) method, and we analyzedthe relationships of genotype frequency distributions and the risk andclinic-pathological features of breast cancer. Statistical analysis wasperformed using SPSS13.0software package. Hardy–Weinberg analysis wasperformed by comparing the genotype frequencies in the control group using the chi-square test. The age and BMI difference of two groups was analyzedby the t-test. Comparison of the IGF2BP2genotype and allele distribution inpatients and healthy controls was performed by Chi-square test. The odds ratio(OR) and95%confidence Interval (CI) were calculated using anunconditional logistic regression model. We assessed the relationship betweenIGF2BP2single nucleotide polymorphisms and the risk of breast cancer andclinic-pathological parameters and adjusted by age and BMI. p<0.05wasconsidered significantly difference.
Results:1.The average age of breast cancer patients was49.1±9.6yearsand48.1±9.9years in the control group of patients. The difference was notstatistically significant. The body mass index was25.5±3.6kg/m2in breastcancer patients and25.4±3.5kg/m2in normal control group, the differencebetween the two groups was statistically significant (P <0.001).
2. The frequencies of GT (43.3%), TT (6.2%), T genotype (GT+TT)(49.5%), and T allele (27.8%) were higher in cancer patients than thefrequencies of GT (36.5%), TT (3.6%), T genotype (40.1%), and T allele(21.8%) in the control groups. Women who were GT heterozygote (ORadj=1.442;95%CI,1.097-1.895) or TT homozygote (ORadj=2.0;95%CI,1.041–3.843), and carriers of T genotype (ORadj=1.494;95%CI,1.146–1.947)or T allele (ORadj=1.391;95%CI,1.120-1.727) were significantly associatedwith breast cancer risk.
3. Stratified analysis by age at diagnosis found that the total number ofage at diagnosis <50years was301in breast cancer patients, of which therewere134cases of rs4402960GT type,16cases of rs4402960TT type and150cases of rs4402960T genotype. The mutation rate was44.5%,5.3%and49.8%, respectively. The total number of age at diagnosis≥50years was263in breast cancer patients, of which there were110cases of rs4402960GT type,19cases of rs4402960TT type and129cases of rs4402960T genotype. Themutation rate was41.8%,7.2%and49%, respectively. The difference ofrs4402960mutation rate between two groups was not statistically significant(P>0.05).
4. Stratified analysis by menopausal status found that the total number ofpre-menopausal breast cancer patients was258, of which there were134casesof rs4402960GT type,12cases of rs4402960TT type and124cases ofrs4402960T allele genotype. The mutation rate was43.4%,4.7%and48.1%,respectively. The total number of post-menopausal breast cancer patients was278, of which there121cases of rs4402960GT type,21cases of rs4402960TT type and142cases of rs4402960T genotype. The mutation rate was43.5%,7.6%and51.1%, respectively. The difference of genotype distributionbetween the two groups was not statistically significant (P>0.05).
5. Stratified analysis by ER status showed that the total number of ERnegative breast cancer patients was179, of which there were71cases ofrs4402960GT type,11cases of rs4402960TT type and82cases of rs4402960T allele genotype. The mutation rate was39.7%,6.1%and45.8%, respectively.The total number of ER positive breast cancer patients was345, of whichthere were150cases of rs4402960GT type,20cases of rs4402960TT typeand170cases of rs4402960T genotype. The mutation rate was43.5%,5.8%and49.3%, respectively. The difference of genotype distribution between thetwo groups was not statistically significant (P>0.05).
6. Stratified analysis by PR status showed that the total number of PRnegative breast cancer patients was227, of which there were92cases ofrs4402960GT type,14cases of rs4402960TT type and106cases ofrs4402960T allele genotype. The mutation rate was40.5%,6.2%and46.7%,respectively. The total number of PR positive breast cancer patients was296,of which there were128cases of rs4402960GT type,17cases of rs4402960TT type and145cases of rs4402960T genotype. The mutation rate was43.2%,5.7%and49%, respectively. The difference of genotype distribution betweenthe two groups was not statistically significant (P>0.05).
7. Stratified analysis by HER-2status showed that the total number ofHER-2negative breast cancer patients was396, of which there were161casesof rs4402960GT type,26cases of rs4402960TT type and187cases ofrs4402960T genotype. The mutation rate was40.7%,6.6%and47.2%, respectively. The total number of HER-2positive breast cancer patients was123, of which there were59cases of rs4402960GT type,4cases of rs4402960TT type and63cases of rs4402960T genotype. The mutation rate was48%,3.3%and51.2%, respectively. The difference of genotype distributionbetween the two groups was not statistically significant (P>0.05).
8.Stratified analysis by P53status showed that the total number of P53negative breast cancer patients was118, of which there were48cases ofrs4402960GT type,5cases of rs4402960TT type and53cases of rs4402960T genotype. The mutation rate was40.7%,4.2%and44.9%, respectively. Thetotal number of P53positive breast cancer patients was327, of which therewere139cases of rs4402960GT type,20cases of rs4402960TT type and159cases of rs4402960T genotype. The mutation rate was42.5%,6.1%and48.6%, respectively. The difference of genotype distribution between the twogroups was not statistically significant (P>0.05).
9. Stratified analysis by Ki-67status showed that the total number ofKi-67negative breast cancer patients was84, of which there were39cases ofrs4402960GT type,2cases of rs4402960TT type and41cases of rs4402960T genotype. The mutation rate was46.4%,2.4%and48.8%, respectively. Thetotal number of Ki-67positive breast cancer patients was379, of which therewere155cases of rs4402960GT type,24cases of rs4402960TT type and179cases of rs4402960T genotype. The mutation rate was40.9%,6.3%and47.2%, respectively. The difference of genotype distribution between the twogroups was not statistically significant (P>0.05).
10. Stratified analysis by lymph node metastasis showed that the totalnumber of breast cancer patients without lymph node metastasis was251, ofwhich there were106cases of rs4402960GT type,17cases of rs4402960TTtype and123cases of rs4402960T genotype. The mutation rate was42.2%,6.8%and49%, respectively. The total number of breast cancer patients withlymph node metastasis was255, of which there were109cases of rs4402960GT type,15cases of rs4402960TT type and124cases of rs4402960Tgenotype. The mutation rate was42.7%,5.9%and48.6%, respectively. The difference of genotype distribution between the two groups was notstatistically significant (P>0.05).
11. Stratified analysis by tumor size showed that the total number ofbreast cancer patients whose tumor diameter≤2cm was248, of which therewere100cases of rs4402960GT type,15cases of rs4402960TT type and115cases of rs4402960T genotype. The mutation rate was40.3%,6%and46.4%,respectively. The total number of breast cancer patients whose tumordiameter>2cm was234, of which there were111cases of rs4402960GT type,14cases of rs4402960TT type and125cases of rs4402960T genotype. Themutation rate was47.4%,6%and53.4%, respectively. The difference ofgenotype distribution between the two groups was not statistically significant(P>0.05).
12. Stratified analysis by histological grade showed that the total numberof histological grade of Ⅰ-Ⅱ breast cancer patients was349, of which therewere141cases of rs4402960GT type,17cases of rs4402960TT type and158cases of rs4402960T genotype. The mutation rate was40.4%,4.9%and45.3%, respectively. The total number of histological grade of Ⅲ breastcancer patients was46, of which there were18cases of rs4402960GT type,5cases of rs4402960TT type and23cases of rs4402960T genotype. Themutation rate was39.1%,10.9%and50%, respectively. The difference ofgenotype distribution between the two groups was not statistically significant(P>0.05).
13. Stratified analysis by tumor clinical staging showed that the totalnumber of stageⅠbreast cancer patients was155, of which there were60cases of rs4402960GT type,11cases of rs4402960TT type and71cases ofrs4402960T genotype. The mutation rate was38.7%,7.1%and45.8%,respectively. The total number of stage Ⅱ breast cancer patients was215, ofwhich there were88cases of rs4402960GT type,10cases of rs4402960TTtype and98cases of rs4402960T genotype. The mutation rate was40.9%,4.7%and45.6%, respectively. The total number of stage Ⅲ breast cancerpatients was156, of which there were76cases of rs4402960GT type,11 cases of rs4402960TT type and87cases of rs4402960T genotype. Themutation rate was48.7%,7.1%and55.8%, respectively. The total number ofstage Ⅳbreast cancer patients was38, of which there were20cases ofrs4402960GT type,3cases of rs4402960TT type and23cases of rs4402960T genotype. The mutation rate was52.6%,7.9%and60.5%, respectively. Thedifference of genotype distribution between the two groups was notstatistically significant (P>0.05).
14. Stratified analysis by molecular typing showed that the total numberof Luminal A type breast cancer patients was74, of which there were33casesof rs4402960GT type,2cases of rs4402960TT type and35cases ofrs4402960T genotype. The mutation rate was44.6%,2.7%and47.3%,respectively. The total number of Luminal B type breast cancer patients was254, of which there were108cases of rs4402960GT type,16cases ofrs4402960TT type and124cases of rs4402960T genotype. The mutation ratewas42.5%,6.3%and48.8%, respectively. The total number of ERBB2+typebreast cancer patients was66, of which there were30cases of rs4402960GTtype,2cases of rs4402960TT type and32cases of rs4402960T genotype.The mutation rate was45.5%,3%and48.5%, respectively. The total numberof Basal-like type breast cancer patients was93, of which there were35casesof rs4402960GT type,6cases of rs4402960TT type and41cases ofrs4402960T genotype. The mutation rate was37.6%,6.5%and44.1%,respectively. The difference of genotype distribution between the two groupswas not statistically significant (P>0.05).
Conclusions:1.There was no significant difference between the age ofbreast cancer patients and normal control cases. BMI of breast cancer patientswas higher than which of the control cases, suggesting that BMI is a riskfactor for breast cancer disease. Normal people should pay attention to dietand exercise to reduce BMI, thereby reducing the risk of breast cancer.
2. There was significant relationship between the IGF2BP2geners4402960polymorphism and risk of breast cancer. The frequencies adjustedby age and BMI of T genotype (GT+TT)(ORadj=1.494,95%CI=1.146-1.947) and T allele (ORadj=1.391,95%CI=1.120-1.727) were significantlyincreased the risk of breast cancer. But there was no association betweenIGF2BP2gene rs4402960polymorphism and age at diagnosis, lymph nodemetastasis, estrogen receptor, progesterone receptor, HER-2receptor status,P53, Ki-67status, tumor size, histological grade, tumor clinical stage andmolecular typing.
目前越来越多的研究表明2型糖尿病与乳腺癌存在着复杂的联系，但具体机制还不是很明确。基因突变被认为与两种疾病均有关，而且相同的基因突变有可能部分解释2型糖尿病与乳腺癌之间的相关性。为了探讨2型糖尿病的易感基因变异是否会增加患乳腺癌的风险，本研究选择了两个2型糖尿病易感基因（TCF7L2，IGF2BP2）的3种寡核苷酸多态性（singlenucleotide polymorphisms，SNP) TCF7L2基因rs7903146、rs12255372和IGF2BP2基因rs4402960，探讨了它们对患乳腺癌风险的影响。转录因子7类似物2（transcription factor7-like2，TCF7L2），又称T细胞转录因子-4（TCF4），其基因位于10q25.2。该基因编码一种含有高迁移率组（HMG）盒的转录因子，参与Wnt/β-catentin信号通路。多项全基因组关联分析研究显示，TCF7L2是2型糖尿病的易感基因之一。Barbara[41]等通过TaqMan等位基因分布技术检测了TCF7L2rs12255372变异在家族性乳腺癌中的作用。研究表明，TCF7L2rs12255372可能影响家族性乳腺癌发病风险。Naidu等[42]对来自医院的马来群岛人群中的387名乳腺癌患者及252名没有任何肿瘤病史的健康女性采用PCR-RFLP方法检测TCF7L2基因多态性的基因型。rs7903146位于TCF7L2基因的3号内含子上，存在CC、CT和TT三种基因型,危险等位基因是T。乳腺癌患者中rs7903146（T）等位基因频率明显高于正常人。CT或TT基因型与乳腺癌风险无关。然而，携带T基因型（CT+TT）或T等位基因的女性表现出了明显增加的乳腺癌风险。rsl2255372位于TCF7L2基因的4号内含子，存在GG、GT和TT3种基因型，危险等位基因是T。GT杂合子或TT纯合子和携带T基因型或T等位基因均与乳腺癌风险无关。rs7903146（T）与淋巴结转移有关，但是rs12255372T等位基因与临床病理特征无关。总之，TCF7L2基因rs7903146（T）变异可能增加乳腺癌风险，有可能成为乳腺癌的候选易感基因。这种变异还可能增加肿瘤远处转移的风险。本课题第二部分研究糖尿病易感基因之一TCF7L2与汉族女性乳腺癌的发病风险。结果表明TCF7L2基因rs7903146、rs12255372多态性与中国汉族女性乳腺癌的发病风险无关。多项研究显示，胰岛素样生长因子2mRNA结合蛋白2（insulin-like growth factor2binding proteins2，IGF2BP2）基因2号内含子上的SNPs rsl470579和rs4402960对2型糖尿病的发展有中度危险性，并在多项人群的重复试验和meta分析中得到证实。但尚未见IGF2BP2基因多态性与乳腺癌关系的报道，因此本课题第三部分研究了IGF2BP2基因rs4402960多态性与中国汉族女性乳腺癌患病风险的关系，结果显示IGF2BP2基因rs4402960多态性可增加中国汉族女性乳腺癌的患病风险。
主要研究内容和结果如下：
第一部分乳腺癌合并2型糖尿病的临床病理特征及预后分析
目的：探讨2型糖尿病与乳腺癌临床病理特征及预后的关系。
方法：随机选取2011年1月-2012年1月于河北医科大学第四医院住院的女性乳腺癌患者240例。将研究对象按是否合并有2型糖尿病分为乳腺癌合并糖尿病组及乳腺癌非糖尿病组,乳腺癌合并糖尿病组包括80例患者,乳腺癌非糖尿病组纳入160例患者。均经外科手术治疗和术后病理切片证实为原发性乳腺癌。查阅病历资料，包括患者姓名、年龄、身高、体重、血糖、初潮年龄、产次、绝经状态、肿瘤大小、淋巴结转移情况、主要免疫组化指标（ER、PR、HER-2及Ki-67）、肿瘤组织学分级、临床分期及分子分型等。采用SPSS13.0统计软件对数据进行分析。计量资料以均数标准差(x s)表示,采用两样本均数比较的t检验;计数资料采用四格表资料的χ2检验。P0.05为差异有统计学意义。
结果：1.乳腺癌合并2型糖尿病组年龄明显高于乳腺癌非糖尿病组，差异有统计学意义，但两组间的BMI无统计学差异。
2.乳腺癌合并2型糖尿病组血糖值明显高于乳腺癌非糖尿病组，差异有统计学意义。
3.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组在初潮年龄、产次方面比较无统计学差异，乳腺癌合并2型糖尿病组绝经后患者明显多于乳腺癌非糖尿病组，两组间比较有统计学差异。
4.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组的肿瘤大小、淋巴结转移情况、ER、PR、HER-2及Ki-67状态等比较均无统计学差异。
5.乳腺癌合并2型糖尿病组与乳腺癌非糖尿病组的临床分期、组织学分级及分子分型比较有统计学差异，乳腺癌合并2型糖尿病组的临床分期、组织学分级及Basal-like型者均高于乳腺癌非糖尿病组，差异有统计学意义。乳腺癌合并2型糖尿病组较乳腺癌非糖尿病组肿瘤临床分期更晚，组织学分级更高，Basal-like型者更常见，预后较差。
结论：1.乳腺癌合并2型糖尿病多见于年龄较大者及绝经后者，对年龄较大的尤其是绝经后的2型糖尿病患者应定期进行乳腺超声及钼靶等检查。
2.乳腺癌合并2糖尿病组与乳腺癌非糖尿病组相比，BMI、初潮年龄、产次、肿瘤大小、淋巴结转移情况、ER、PR、HER-2及Ki-67状态等均无明显统计学差异。但乳腺癌合并2型糖尿病患者的临床分期较晚，组织学分级较高，Basal-like型者更常见，预后较差。2型糖尿病是乳腺癌患者预后不良的危险因素。第二部分TCF7L2基因多态性与汉族女性乳腺癌风险的相关性研究
目的：探讨2型糖尿病的易感基因之一核转录因子7类似物2（TCF7L2）的多态性与汉族女性乳腺癌发病风险的关系。
方法：采用病例对照研究，抽取河北医科大学第四医院住院的汉族女性乳腺癌患者及来自白求恩国际和平医院同期健康体检汉族女性的外周血，提取基因组DNA，采用聚合酶链反应-连接酶检测反应(polymerasechain reaction-ligase detection reaction，PCR-LDR)分型方法检测TCF7L2基因rs7903146、rs12255372多态性，比较基因型频率分布和患病风险及临床病理特征的关系。采用SPSS13.0软件包进行统计学分析。采用χ2检验对正常对照组的基因型分布频率进行Hardy-Weinberg平衡检验。病例组和对照组的年龄、BMI差异采用t检验。采用χ2检验比较TCF7L2各基因型在病例与对照组之间分布的差异。采用Logistic回归计算比值比(Odds Ratio, OR)及其95%可信区间(Confidence Interval, CI)评估TCF7L2单核苷酸多态性与乳腺癌患病风险及临床病理参数的关系,并以年龄、BMI进行校正。P0.05表示差异有统计学意义。
结果：1.乳腺癌组患者平均年龄为49.1±9.6岁，正常对照组患者年龄为48.1±9.9岁，两组间差异无统计学意义。乳腺癌组患者BMI为25.5±3.6kg/m2，正常对照组患者BMI为25.4±3.5kg/m2，两组间差异有统计学意义（P0.001）。
2.乳腺癌组和对照组TCF7L2基因rs7903146C/T的基因型频率分布情况：两组人群均未检测出TT基因型,乳腺癌组CC、CT两种基因型频率分别为92.7％和7.3％，与对照组各基因型频率89.3%、10.7%相比，差异无显著性(χ2=3.369P=0.066)。与CC基因型比较，携带CT基因型未显著改变乳腺癌的发病风险(OR=1.522，95%CI=0.97-2.389)。乳腺癌组和对照组TCF7L2基因rs12255372G/T的基因型频率分布情况：乳腺癌组GG、GT两种基因型频率分别为98.2％和1.8％，与对照组各基因型频率97.7%、2.3%相比，差异无显著性(χ2=0.312P=0.577)。与GG基因型比较，携带GT基因型未显著改变乳腺癌的发病风险(OR=1.295，95%CI=0.512-3.217)。
3.按诊断时年龄进行分层分析发现,诊断时年龄<50岁的乳腺癌患者共301例，其中rs7903146CT型有14例，突变率为4.7%；rs12255372GT型有3例，突变率为1%。诊断时年龄≥50岁的乳腺癌患者共263例，rs7903146CT型有27例，突变率为9.3%；rs12255372GT型有7例，突变率为2.7%。诊断时年龄≥50岁的乳腺癌患者rs7903146位点突变率明显高于诊断时年龄<50岁者，两组患者间基因型分布有统计学差异（P0.05），OR值为2.345(95%CI=1.202-4.575)；诊断时年龄≥50岁的乳腺癌患者rs12255372位点突变率与诊断时年龄50岁者相比无统计学差异。
4.按绝经状态分层分析发现，绝经前的乳腺癌患者共258例，其中rs7903146CT型有12例，突变率为4.7%；绝经后的乳腺癌患者共278例，其中CT型有26例，突变率为9.4%。两组患者间基因型分布有统计学差异（P0.05）。绝经后组患者发生基因突变的可能性明显高于绝经前组，OR值为2.115(95%CI=1.044-4.286);绝经前患者中rs12255372GT型有1例，突变率为0.4%；绝经后的乳腺癌患者中rs12255372GT型有7例，突变率为2.5%。两组患者间基因型分布无统计学差异（P>0.05）。
5.按ER状态分层分析显示，ER阴性的乳腺癌患者共179例，其中rs7903146CT型有10例，突变率为5.6%；rs12255372GT型有2例，突变率为1.1%。ER阳性的乳腺癌患者共345例，其中CT型有29例，突变率为8.4%；rs12255372GT型有8例，突变率为2.3%。两组患者间基因型分布均无统计学差异（P>0.05）。
6.按PR状态分层分析发现，PR阴性的乳腺癌患者共227例，其中rs7903146CT型有17例，突变率为7.5%；GT型有5例，突变率为2.2%。PR阳性的乳腺癌患者共296例，其中rs7903146CT型有22例，突变率为7.4%；rs12255372GT型有5例，突变率为1.7%。两组患者间基因型分布均无统计学差异（P>0.05）。
7.按HER-2状态分层分析发现，HER-2阴性的乳腺癌患者共396例，其中rs7903146CT型有27例，突变率为6.8%；rs12255372GT型有8例，突变率为2%。HER-2阳性的乳腺癌患者共123例，其中rs7903146GT型有11例，突变率为8.9%；rs12255372GT型有2例，突变率为1.6%。两组患者间基因型分布均无统计学差异（P>0.05）。
8.按P53状态分层分析显示，P53阴性的乳腺癌患者共118例，其中rs7903146CT型有9例，突变率为7.6%；rs12255372GT型有3例，突变率为2.5%。P53阳性的乳腺癌患者共327例，其中rs7903146CT型有26例，突变率为8%；rs12255372GT型有4例，突变率为1.2%。两组患者间基因型分布均无统计学差异（P>0.05）。
9.按Ki-67状态分层分析显示，Ki-67阴性的乳腺癌患者共84例，其中rs7903146CT型有5例，突变率为6%；rs12255372GT型有1例，突变率为1.2%。Ki-67阳性的乳腺癌患者共379例，其中rs7903146CT型有30例，突变率为7.9%；rs12255372GT型有6例，突变率为1.6%。两组患者间基因型分布无统计学差异（P>0.05）。
10.按有无淋巴结转移分层分析显示，无淋巴结转移的乳腺癌患者共251例，其中rs7903146CT型有16例，突变率为6.4%；rs12255372GT型有5例，突变率为2%。有淋巴结转移的乳腺癌患者共255例，其中rs7903146CT型有20例，突变率为7.8%；rs12255372GT型有3例，突变率为1.2%。两组患者间基因型分布均无统计学差异（P>0.05）。
11.按肿瘤大小分层分析显示，肿瘤直径≤2cm的乳腺癌患者共248例，其中rs7903146CT型有14例，突变率为5.6%；rs12255372GT型有1例，突变率为0.4%。肿瘤直径>2cm的乳腺癌患者共234例，其中rs7903146CT型有20例，突变率为8.5%；rs12255372GT型有6例，突变率为2.5%。两组患者间基因型分布均无统计学差异（P>0.05）。
12.按组织学分级分层分析发现，组织学分级为Ⅰ-Ⅱ级的乳腺癌患者共349例，其中rs7903146CT型有29例，突变率为8.3%；rs12255372GT型有7例，突变率为7%。组织学分级为Ⅲ级的乳腺癌患者共46例，其中rs7903146CT型有1例，突变率为2.2%；rs12255372GT型有0例，突变率为0%。两组患者间基因型分布均无统计学差异（P>0.05）。
13.按肿瘤临床分期分层分析显示，临床分期为Ⅰ期的乳腺癌患者共155例，其中rs7903146CT型有9例，突变率为5.8%；rs12255372GT型有2例，突变率为1.3%。临床分期为Ⅱ期的乳腺癌患者共215例，其中rs7903146CT型有19例，突变率为8.8%；rs12255372GT型有5例，突变率为2.3%。临床分期为Ⅲ期的乳腺癌患者共156例，其中rs7903146CT型有10例，突变率为6.4%；rs12255372GT型有2例，突变率为1.3%。临床分期为Ⅳ期的乳腺癌患者共38例，其中rs7903146CT型有3例，突变率为7.9%；rs12255372GT型有1例，突变率为2.6%。两组患者间基因型分布无统计学差异（P>0.05）。
14.按分子分型分层分析显示，Luminal A型的乳腺癌患者共74例，其中rs7903146CT型有5例，突变率为6.8%；rs12255372GT型有1例，突变率为1.4%。Luminal B型的乳腺癌患者共254例，其中rs7903146CT型有24例，突变率为9.4%；rs12255372GT型有6例，突变率为2.4%。ERBB2+型的乳腺癌患者共66例，其中rs7903146CT型有2例，突变率为3%；rs12255372GT型有0例，突变率为0%。Basal-like型的乳腺癌患者共93例，其中rs7903146CT型有6例，突变率为6.5%；rs12255372GT型有2例，突变率为2.2%。两组患者间基因型分布无统计学差异（P>0.05）。
结论：1.乳腺癌组患者与正常对照组间年龄无统计学差异，乳腺癌组患者的BMI高于正常对照组，提示BMI是乳腺癌患病的危险因子，正常人群应该注意控制饮食、加强锻炼以减轻BMI，从而降低患乳腺癌的风险。
2. TCF7L2基因多态位点rs7903146突变在绝经后患者及诊断时年龄≥50岁者明显高于绝经前者及诊断时年龄<50岁者，但TCF7L2基因多态位点rs12255372基因突变与绝经状态及诊断时年龄无关。
3. TCF7L2基因多态位点rs7903146及rs12255372基因多态性与乳腺癌的发病风险无关，且与淋巴结转移情况、雌孕激素受体、HER-2受体状态、P53、Ki-67状态、肿瘤大小、组织学分级、肿瘤分期及分子分型均无明显相关性。第三部分IGF2BP2基因多态性与汉族女性乳腺癌发病风险的关联研究
目的：探讨2型糖尿病的易感基因之一胰岛素样生长因子2mRNA结合蛋白2（IGF2BP2）的多态性与乳腺癌发病风险的关系。
方法：采用病例对照研究，抽取河北医科大学第四医院住院的汉族女性乳腺癌患者及来自白求恩国际和平医院同期健康体检汉族女性的外周血，提取基因组DNA，采用聚合酶链反应-连接酶检测反应(polymerasechain reaction-ligase detection reaction，PCR-LDR)分型方法检测IGF2BP2基因rs4402960多态性，比较基因型频率分布和患病风险及临床病理特征的关系。采用SPSS13.0软件包进行统计学分析。采用χ2检验对对照组的基因型分布频率进行Hardy-Weinberg平衡检验。病例组和对照组的年龄、BMI差异采用t检验。采用χ2检验比较IGF2BP2各基因型在病例与对照组之间分布的差异。采用Logistic回归计算比值比(Odds Ratio,OR)及其95%可信区间(Confidence Interval, CI)评估IGF2BP2单核苷酸多态性与乳腺癌患病风险及临床病理参数的关系,并以年龄、BMI进行校正。所有统计检验均为双侧概率检验, P0.05表示差异有统计学意义。
结果：1.乳腺癌组患者平均年龄为49.1±9.6岁，正常对照组患者年龄为48.1±9.9岁，两组间差异无统计学意义。乳腺癌组患者BMI为25.5±3.6kg/m2，正常对照组患者BMI为25.4±3.5kg/m2，两组间差异有统计学意义（P0.001）。
2.乳腺癌组和对照组IGF2BP2基因rs4402960G/T的基因型频率分布情况：病例组的GT(43.3%)、TT(6.2%)频率、T基因型（GT+TT）（49.5%）及T等位基因（27.8%）明显高于对照组的GT(36.5%)、TT(3.6%)频率、T基因型（GT+TT）（40.1%）及T等位基因（21.8%）。 GT（ORadj=1.442;95%CI,1.097-1.895）、TT（ORadj=2.0;95%CI,1.041-3.843）基因型，T基因型携带者（GT+TT）（ORadj=1.494;95%CI,1.146-1.947）及T等位基因（ORadj=1.391;95%CI,1.120-1.727）均明显增加乳腺癌的发病风险。
3.按诊断时年龄进行分层分析发现,诊断时年龄50岁的乳腺癌患者共301例，其中GG型有151例(50.2%)，GT型有134例(44.5%)， TT型有16例（5.3%），T基因型携带者为150例（49.8%）；诊断时年龄≥50岁的乳腺癌患者共263例，其中GG型有134例(51%)，GT型有110例(41.8%)，TT型有19例（7.2%）T基因型携带者为129例（49%）。两组患者间基因型分布无统计学差异（P>0.05）。
4.按绝经状态分层分析发现，绝经前的乳腺癌患者共258例，其中GG型有134例（51.9%），GT型有112例（43.4%），TT型有12例（4.7%），T基因型携带者为124例（48.1%）；绝经后的乳腺癌患者共278例，其中GG型有136例（48.9%），GT型有121例（43.5%），TT型有21例（7.6%），T基因型携带者为142例（51.1%）。两组患者间基因型分布无统计学差异（P>0.05）。
5.按ER状态分层分析显示，ER阴性的乳腺癌患者共179例，其中GG型有97例（54.2%），GT型有71例（39.7%），TT型有11例（6.1%），T基因型携带者为82例（45.8%）；ER阳性的乳腺癌患者共345例，其中GG型有175例（50.7%），GT型有150例（43.5%），TT型有20例（5.8%），T基因型携带者为170例（49.3%）。两组患者间基因型分布无统计学差异（P>0.05）。
6.按PR状态分层分析发现，PR阴性的乳腺癌患者共227例，其中GG型有121例(53.3%)，GT型有92例(40.5%)，TT型有14例（6.2%），T基因型携带者为106例（46.7%）；PR阳性的乳腺癌患者共296例，GG型有151例(51%)，GT型有128例(43.2%)，TT型有17例（5.7%），T基因型携带者为145例（49%）。两组患者间基因型分布无统计学差异（P>0.05）。
7.按HER-2状态分层分析发现，HER-2阴性的乳腺癌患者共396例，GG型有209例(52.8%)，GT型有161例(40.7%)，TT型有26例（6.6%），T基因型携带者为187例（47.2%）；HER-2阳性的乳腺癌患者共123例，GG型有60例(48.8%)，GT型有59例(48%)，TT型有4例（3.3%），T基因型携带者为63例（51.2%）。两组患者间基因型分布无统计学差异（P>0.05）。
8.按P53状态分层分析显示，P53阴性的乳腺癌患者共118例，其中GG型有65例(55.1%)，GT型有48例(40.7%)，TT型有5例（4.2%），T基因型携带者为53例（44.9%）；P53阳性的乳腺癌患者共327例，GG型有168例(51.4%)，GT型有139例(42.5%)，TT型有20例（6.1%），T基因型携带者为159例（48.6%）。两组患者间基因型分布无统计学差异（P>0.05）。
9.按Ki-67状态分层分析显示，Ki-67阴性的乳腺癌患者共84例，GG型有43例(51.2%)，GT型有39例(46.4%)，TT型有2例（2.4%），T基因型携带者为41例（48.8%）；Ki-67阳性的乳腺癌患者共379例，GG型有200例(52.8%)，GT型有155例(40.9%)，TT型有24例（6.3%），T基因型携带者为179例（47.2%）。两组患者间基因型分布无统计学差异（P>0.05）。
10.按有无淋巴结转移分层分析显示，无淋巴结转移的乳腺癌患者共251例，GG型有128例(51%)，GT型有106例(42.2%)，TT型有17例（6.8%），T基因型携带者为123例（49%）；有淋巴结转移的乳腺癌患者共255例，GG型有131例(51.4%)，GT型有109例(42.7%)，TT型有15例（5.9%），T基因型携带者为124例（48.6%）。两组患者间基因型分布无统计学差异（P>0.05）。
11.按肿瘤大小分层分析显示，肿瘤直径≤2cm的乳腺癌患者共248例，GG型有133例(53.6%)，GT型有100例(40.3%)，TT型有15例（6%），T基因型携带者为115例（46.4%）；肿瘤直径>2cm的乳腺癌患者共234例，GG型有109例(46.6%)，GT型有111例(47.4%)，TT型有14例（6%），T基因型携带者为125例（53.4%）。两组患者间基因型分布无统计学差异（P>0.05）。
12.按组织学分级分层分析发现，组织学分级为Ⅰ-Ⅱ级的乳腺癌患者共349例，GG型有191例(54.7%)，GT型有141例(40.4%)，TT型有17例（4.9%），T基因型携带者为158例（45.3%）；组织学分级为Ⅲ级的乳腺癌患者共46例，GG型有23例(50%)，GT型有18例(39.1%)，TT型有5例（10.9%），T基因型携带者为23例（50%）。两组患者间基因型分布无统计学差异（P>0.05）。
13.按肿瘤临床分期分层分析显示，临床分期为Ⅰ期的乳腺癌患者共155例，其中GG型有84例(54.2%)，GT型有60例(38.7%)，TT型有11例（7.1%），T基因型携带者为71例（45.8%）；临床分期为Ⅱ期的乳腺癌患者共215例，GG型有117例(54.4%)，GT型有88例(40.9%)，TT型有10例（4.7%），T基因型携带者为98例（45.6%）；临床分期为Ⅲ期的乳腺癌患者共156例，GG型有69例(44.2%)，GT型有76例(48.7%)，TT型有11例（7.1%），T基因型携带者为87例（55.8%）；临床分期为Ⅳ期的乳腺癌患者共38例，GG型有15例(39.5%)，GT型有20例(52.6%)，TT型有3例（7.9%），T基因型携带者为23例（60.5%）。两组患者间基因型分布无统计学差异（P>0.05）。
14.按分子分型分层分析显示，Luminal A型的乳腺癌患者共74例，其中GG型有39例(52.7%)，GT型有33例(44.6%)，TT型有2例（2.7%），T基因型携带者为35例（47.3%）；Luminal B型的乳腺癌患者共254例，GG型有130例(51.2%)，GT型有108例(42.5%)，TT型有16例（6.3%），T基因型携带者为124例（48.8%）；ERBB2+型的乳腺癌患者共66例，GG型有34例(51.5%)，GT型有30例(45.5%)，TT型有2例（3%），T基因型携带者为32例（48.5%）。Basal-like型的乳腺癌患者共93例，GG型有52例(55.9%)，GT型有35例(37.6%)，TT型有6例（6.5%），T基因型携带者为41例（44.1%）；两组患者间基因型分布无统计学差异（P>0.05）。
结论：1.乳腺癌组患者与正常对照组间年龄比较无统计学差异，乳腺癌组患者的BMI高于正常对照组，提示BMI是乳腺癌患病的危险因子，正常人群应该注意控制饮食、加强锻炼以减轻BMI，从而降低患乳腺癌的风险。
2. IGF2BP2基因多态位点rs4402960基因多态性与乳腺癌的发病风险有关，经校正年龄及BMI后， T基因型携带者（GT+TT）（ORadj=1.494;95%CI,1.146-1.947）及T等位基因（ORadj=1.391;95%CI,1.120-1.727）均明显增加乳腺癌的发病风险。但与诊断时年龄、绝经状态、淋巴结转移情况、雌孕激素受体、HER-2受体状态、P53、Ki-67状态、肿瘤大小、组织学分级及肿瘤临床分期均无明显相关性。
Breast cancer is one of the most common malignant tumors in females.With an annual incidence rate increased by more than3%in the past few years,it is the number one cause in morbidity among all the malignant tumor typesin Chinese females. Diabetes, often referred to as diabetes mellitus, is a groupof diseases characterized by glycometabolism disorders and caused by geneticas well as environmental reasons. Insulin deficiency and dysfunction may acttogether or independently to induce metabolic disorders of carbohydrates,lipids, proteins, water and electrolytes. There have recently been drasticincreases in the incidence rate of diabetes in a worldwide range, and China isbecoming one of the countries with the highest diabetes morbidity, where thediabetes population is expected to exceed that of India and become No.1in2020. There is Meta analysis that shows the corresponding risk of breastcancer in patients diagnosed with type2diabetes is1.2-1.5fold of that of thenormal people. In the first part of this research, to investigate the effects oftype2diabetes mellitus on the clinico-pathological characteristics andprognosis of breast cancer, we retrospectively analyzed the medical records of80breast cancer patients with type2diabetes and160non-diabetic breastcancer patients.
More and more previous investigations indicate that there might becomplicated correlations between type2diabetes and breast cancers, but theunderlying mechanism remains to be explored. Gene mutations are believed tobe correlated with both of the above two diseases, and similar gene mutationsmight partially explain the correlation between diabetes and breast cancer. Thetranscription factor7-like2(TCF7L2) gene is located on the chromosome10q25.2, which was also known previously as TCF-4. The gene encodes ahigh mobility group box-containing transcription factor which is involved in Wnt/β-catenin signaling pathway. The analysis of multiple whole genomeassociation illustrates that TCF7L2is one of the susceptibility genes for type2diabetes. Barbara et al. investigated the effect of the TCF7L2rs12255372variant on familial breast cancer (BC) risk by means of TaqMan allelicdiscrimination. Their results suggest a possible influence of TCF7L2rs12255372on the risk of familial BC. Genotyping of TCF7L2polymorphisms was performed on387breast cancer patients and252healthywomen who had no history of any malignancy using polymerase chainreaction–restriction fragment length polymorphism (PCR–RFLP) method in ahospital-based Malaysian population by Naidu et al. The allele frequency ofrs7903146(T) polymorphism was significantly higher in the cancer patientsthan normal individuals. No significant association was demonstrated betweenCT and TT genotype and breast cancer risk. However, women who werecarriers of T allele or T allele genotype showed significant increased risk ofbreast cancer. The rs7903146(T) allele genotype was significantly associatedwith nodal involvement but rs12255372(T) allele genotype was not associatedwith the clinico-pathologic characteristics. In conclusion, rs7903146(T)variant may elevate the risk of breast cancer, thus could be a potentialcandidate for breast cancer susceptibility. The variant may also increase themetastatic potential of the tumor. The second part of this study is to investigatethe association of TCF7L2and the risk of breast cancer. The results showedthat the gene TCF7L2rs7903146, rs12255372polymorphisms were notassociated with the risk of breast cancer in Chinese Han. Many studies haveshown that the SNPs rs1470579and rs4402960in the second intron ofIGF2BP2gene is of medium risk in the development of type2diabetesmellitus, and such results have been proven by investigations and Metaanalysis repeated in various populations. However, there have not been anyreports about the correlations between IGF2BP2gene polymorphism andbreast cancer, and therefore we investigated the polymorphism of IGF2BP2gene, rs4402960, and its correlation to the risk of breast cancer in Chinesefemales of Han nationality. The research contents and results are as follows: Part I The clinico-pathologic characteristics and prognosis in breastcancer patients with type2diabetes
Objective: To investigate the association of type2diabetes mellitus onthe clinico-pathologic characteristics and prognosis of breast cancer.
Methods: A case-control study, which includes240female breast cancerPatients, who were in-hospital in the fourth affiliated hospital of HebeiMedical University from January2011to January2012. The Patients weredivided into two groups according to incidence of type2diabetes. Breastcancer and diabetes group included80patients, non-diabetic group included160patients. They all had been operated and their pathology slices werediagnosed primary breast. We reviewed patients’ medical records, includingpatient name, age, height, weight, blood glucose, age at menarche, parity,menopausal status, tumor size, lymph node metastasis, the major indexesimmunohistochemistry (ER, PR, HER-2, Ki-67), tumor histological grade,clinical stage and molecular typing, etc. SPSS13.0statistical software wasused to do the statistics analysis. Measurement data were expressed as mean standard deviation, and compared using t-test; count data tables were analyzedby the x2test. P <0.05was considered significantly difference.
Results:1. Breast cancer patients with type2diabetes were older thanthose in non-diabetic group, the difference was statistically significant, butthere was no significant difference in BMI between the two groups.
2. In breast cancer patients with type2diabetes, blood glucose weresignificantly higher than the non-diabetic patients, the difference wasstatistically significant.
3. There were no significant difference in age at menarche and paritybetween Breast cancer patients with type2diabetes mellitus and non-diabeticpatients, postmenopausal patients in the group of breast cancer patients withtype2diabetes have significantly more than those in non-diabetic patientsgroup, there were significant differences between the two groups.
4. There was no significant difference in the distribution of tumor size,lymph node metastasis, ER, PR, HER-2and Ki-67status between group of breast cancer patients with type2diabetes and non-diabetic group.
5. Significant differences in the distribution of clinical stage, histologicalgrade and molecular typing between group of breast cancer patients with type2diabetes and non-diabetic group, the higher clinical stage, histological gradeand Basal-like type were found in group of breast cancer patients with type2diabetes than in non-diabetic group. The difference was statisticallysignificant.
Conclusions:1. Breast cancer with type2diabetes is more common inpatients with older age and post menopause. Elder type2diabetes patientsespecially for postmenopausal should be regularly examined by breastultrasound and mammography.
2. There was no significant difference in the distribution of BMI, age atmenarche, parity, tumor size, lymph node metastasis, ER, PR, HER-2andKi-67status between group of breast cancer patients with type2diabetes andnon-diabetic group. The higher clinical stage, histological grade and Basal-liketype were found in group of breast cancer patients with type2diabetes than innon-diabetic group. Type2diabetes is the risk factor of breast cancer withpoor prognosis. Female breast cancer patients with type2diabetes have laterclinical stage and poor prognosis.Part II The association of TCF7L2gene polymorphism with breast cancerrisk in Chinese Han female
Objective: To investigate the relationship of nuclear transcription factor7like2(TCF7L2) gene which is one of diabetes susceptibility genespolymorphism and risk of breast cancer.
Methods: In this case-control study, peripheral blood was extracted fromwomen with breast cancer hospitalized in The Fourth Hospital of HebeiMedical University and from the same period healthy volunteers in BethuneInternational Peace Hospital. Genomic DNA was extracted from peripheralblood. The TCF7L2rs7903146, rs12255372polymorphism were detected byPolymerase chain reaction-ligase detection reaction (PCR-LDR) method, andwe analyzed the relationships of genotype frequency distributions and the risk and clinic-pathological features of breast cancer. Statistical analysis wasperformed using SPSS13.0software package. Hardy–Weinberg analysis wasperformed by comparing the genotype frequencies in the control group usingthe chi-square test. The age and BMI difference of two groups was analyzedby the t-test. Comparison of the TCF7L2genotype and allele distribution inpatients and healthy controls was performed by Chi-square test. The odds ratio(OR) and95%confidence Interval (CI) were calculated using anunconditional logistic regression model. We assessed the relationship betweenTCF7L2single nucleotide polymorphisms and the risk of breast cancer andclinic-pathological parameters adjusted by age and BMI. P <0.05wasconsidered significantly difference.
Results:1.The average age of breast cancer patients was49.1±9.6yearsand48.1±9.9years in the control group of patients. The difference was notstatistically significant. The body mass index was25.5±3.6kg/m2in breastcancer patients and25.4±3.5kg/m2in normal control group, the differencebetween the two groups was statistically significant (P <0.001).
2. Two groups were not detected TT genotype.The genotype frequenciesof the TCF7L2rs7903146CC and CT in patients with breast cancer andcontrols were92.7％,7.3％and89.3%,10.7%respectively. No statisticallysignificant difference in the TCF7L2genotype distribution was demonstratedbetween cases and controls (χ2=3.369P=0.066). Compared to the CCgenotype, the CT genotype did not increase the risk of developing breastcancer, the odds ratio were1.522(95%CI=0.97-2.389). The allele frequenciesof the TCF7L2rs12255372CC and CT in patients with breast cancer andcontrols were98.2％,1.8％and97.7%,2.3%respectively. No statisticallysignificant difference in the TCF7L2allele distribution was demonstratedbetween cases and controls (χ2=0.312P=0.577). Compared to the CCgenotype, the CT genotype did not increase the risk of developing breastcancer, the odds ratio were1.295(95%CI=0.512-3.217).
3. Stratified analysis by age at diagnosis found that the total number ofage at diagnosis <50years was301in breast cancer patients, of which there were14cases of rs7903146CT type. The mutation rate was4.7%. There were3cases of rs12255372GT type in301cases. The mutation rate was1%.Thetotal number of age at diagnosis≥50years was263in breast cancer patients,of which there were27cases of rs7903146CT type. The mutation rate was9.3%. There were7cases of rs12255372GT type in263cases. The mutationrate was2.7%. The mutation rate of TCF7L2rs7903146was significantlyhigher in breast cancer patients whose age at diagnosis≥50years than thoseage at diagnosis <50years. The difference of genotype between the twogroups was statistically significant (P <0.05), the odds ratio were2.345(95%CI=1.202-4.575). The difference of rs12255372mutation rate between twogroups was not statistically significant (P>0.05).
4. Stratified analysis by menopausal status found that the total number ofpre-menopausal breast cancer patients was258, of which there were12casesof rs7903146CT type. The mutation rate was4.7%. The total number ofpost-menopausal breast cancer patients was278, of which there are26casesof CT type. The difference of genotype between the two groups wasstatistically significant (P<0.05). The rs7903146mutation rate inpostmenopausal breast cancer patients than those in pre-menopausal breastcancer patients, the odds ratio were2.115(95%CI=1.044-4.286). There were12cases of rs7903146CT type. The mutation rate was4.7%. There were onecases of GT type in pre-menopausal breast cancer patients. The mutation ratewas0.4%. There were seven cases of GT type in post-menopausal breastcancer patients. The mutation rate was2.5%. The difference in genotypedistribution between the two groups was not statistically significant (P>0.05).
5. Stratified analysis by ER status showed that the total number of ERnegative breast cancer patients was179, of which there were12cases ofrs7903146CT type. The mutation rate was5.6%. There were two cases ofrs12255372GT type in179cases. The mutation rate was1.1%.The totalnumber of ER positive breast cancer patients was345, of which there are29cases of rs7903146CT type. The mutation rate was8.4%. There were eightcases of rs12255372GT type in345cases. The mutation rate was2.3%. The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
6. Stratified analysis by PR status showed that the total number of PRnegative breast cancer patients was227, of which there were17cases ofrs7903146CT type. The mutation rate was7.5%. There were five cases ofrs12255372GT type in227cases. The mutation rate was2.2%.The totalnumber of PR positive breast cancer patients was296, of which there are22cases of rs7903146CT type. The mutation rate was7.4%. There were fivecases of rs12255372GT type in296cases. The mutation rate was1.7%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
7. Stratified analysis by HER-2status showed that the total number ofHER-2negative breast cancer patients was396, of which there were27casesof rs7903146CT type. The mutation rate was6.8%. There were eight cases ofrs12255372GT type in227cases. The mutation rate was2%.The total numberof HER-2positive breast cancer patients was123of which there are11casesof rs7903146CT type. The mutation rate was8.9%. There were two cases ofrs12255372GT type in123cases. The mutation rate was1.6%. The differencein genotype distribution between the two groups was not statisticallysignificant (P>0.05).
8. Stratified analysis by P53status showed that the total number of P53negative breast cancer patients was118, of which there were nine cases ofrs7903146CT type. The mutation rate was7.6%. There were three cases ofrs12255372GT type in118cases. The mutation rate was2.5%.The totalnumber of P53positive breast cancer patients was327, of which there are26cases of rs7903146CT type. The mutation rate was8%. There were four casesof rs12255372GT type in327cases. The mutation rate was1.2%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
9. Stratified analysis by Ki-67status showed that the total number ofKi-67negative breast cancer patients was84, of which there were five cases of rs7903146CT type. The mutation rate was6%. There were one cases ofrs12255372GT type in84cases. The mutation rate was1.2%.The totalnumber of Ki-67positive breast cancer patients was463, of which there are30cases of rs7903146CT type. The mutation rate was7.9%. There were sixcases of rs12255372GT type in379cases. The mutation rate was1.6%. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
10. Stratified analysis by lymph node metastasis showed that the totalnumber of breast cancer patients without lymph node metastasis was251, ofwhich there were16cases of rs7903146CT type. The mutation rate was6.4%.There were five cases of rs12255372GT type in251cases. The mutation ratewas2%.The total number of breast cancer patients with lymph nodemetastasis was255, of which there are20cases of rs7903146CT type. Themutation rate was7.8%. There were three cases of rs12255372GT type in255cases. The mutation rate was1.2%. The difference in genotype distributionbetween the two groups was not statistically significant (P>0.05).
11. Stratified analysis by tumor size showed that the total number ofbreast cancer patients whose tumor diameter≤2cm was248, of which therewere14cases of rs7903146CT type. The mutation rate was5.6%. There were1cases of rs12255372GT type in248cases. The mutation rate was0.4%.Thetotal number of breast cancer patients whose tumor diameter>2cm was234,of which there are20cases of rs7903146CT type. The mutation rate was8.5%. There were six cases of rs12255372GT type in234cases. The mutationrate was2.5%. The difference in genotype distribution between the two groupswas not statistically significant (P>0.05).
12. Stratified analysis by histological grade showed that the total numberof histological grade of Ⅰ-Ⅱ breast cancer patients was349, of which therewere29cases of rs7903146CT type. The mutation rate was8.3%. There wereseven cases of rs12255372GT type in349cases. The mutation rate was7%.The total number of histological grade of Ⅲ breast cancer patients was46, of which there are1cases of rs7903146CT type. The mutation rate was 2.2%. There were zero cases of rs12255372GT type in234cases. Thedifference in genotype distribution between the two groups was notstatistically significant (P>0.05).
13. Stratified analysis by tumor clinical staging showed that the totalnumber of stage Ⅰ breast cancer patients was155, of which there were ninecases of rs7903146CT type. The mutation rate was5.8%. There were twocases of rs12255372GT type in155cases. The mutation rate was1.3%.Thetotal number of stage Ⅱ breast cancer patients was215, of which there are19cases of rs7903146CT type. The mutation rate was8.8%. There were fivecases of rs12255372GT type in215cases. The mutation rate was2.3%. Thetotal number of stage Ⅲ breast cancer patients was156, of which there are10cases of rs7903146CT type. The mutation rate was6.4%. There were twocases of rs12255372GT type in156cases. The mutation rate was1.3%. Thetotal number of stage Ⅳbreast cancer patients was38, of which there arethree cases of rs7903146CT type. The mutation rate was7.9%. There wereone cases of rs12255372GT type in38cases. The mutation rate was2.6%.The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
14. Stratified analysis by molecular typing showed that the total numberof Luminal A type breast cancer patients was74, of which there were fivecases of rs7903146CT type. The mutation rate was6.8%. There were onecases of rs12255372GT type in74cases. The mutation rate was1.4%.Thetotal number of Luminal B type breast cancer patients was254, of which thereare24cases of rs7903146CT type. The mutation rate was9.4%. There weresix cases of rs12255372GT type in254cases. The mutation rate was2.4%.The total number of ERBB2+type breast cancer patients was66, of whichthere are two cases of rs7903146CT type. The mutation rate was3%. Therewere zero cases of rs12255372GT type in66cases. The mutation rate was0%.The total number of Basal-like type breast cancer patients was93, of whichthere are six cases of rs7903146CT type. The mutation rate was6.5%. Therewere two cases of rs12255372GT type in38cases. The mutation rate was 2.2%. The difference in genotype distribution between the two groups was notstatistically significant (P>0.05).
Conclusions:1.There was no significant difference between the age ofbreast cancer patients and normal control cases. BMI of breast cancer patientswas higher than which of the control cases, suggesting that BMI is a riskfactor for breast cancer disease. Normal people should pay attention to dietand exercise to decline BMI, thereby reducing the risk of breast cancer.
2. The mutation of TCF7L2gene rs7903146polymorphisms in thepost-menopausal and age at diagnosis≥50years patients was significantlyhigher than the pre-menopause and age at diagnosis <50years patients. Themutation of TCF7L2gene rs12255372polymorphisms was not associatedwith menopausal status and age at diagnosis.
3. There was no relationship between the TCF7L2gene rs7903146andrs12255372polymorphisms and risk of breast cancer, lymph node metastasis,estrogen receptor, progesterone receptor, HER-2receptor status, P53, Ki-67status, tumor size, histological grade, tumor stage and molecular typing.Part III The association of IGF2BP2gene polymorphism with breastcancer risk in Chinese Han female
Objective: To investigate the relationship of Insulin-like growth factor2mRNA binding protein2(IGF2BP2) which is one of the diabetessusceptibility genes polymorphism and risk of breast cancer.
Methods: In this case-control study, peripheral blood was extracted fromwomen with breast cancer hospitalized in The Fourth Hospital of HebeiMedical University and from the same period healthy volunteers in BethuneInternational Peace Hospital. Genomic DNA was extracted from peripheralblood. The IGF2BP2rs4402960polymorphism was detected by Polymerasechain reaction-ligase detection reaction (PCR-LDR) method, and we analyzedthe relationships of genotype frequency distributions and the risk andclinic-pathological features of breast cancer. Statistical analysis wasperformed using SPSS13.0software package. Hardy–Weinberg analysis wasperformed by comparing the genotype frequencies in the control group using the chi-square test. The age and BMI difference of two groups was analyzedby the t-test. Comparison of the IGF2BP2genotype and allele distribution inpatients and healthy controls was performed by Chi-square test. The odds ratio(OR) and95%confidence Interval (CI) were calculated using anunconditional logistic regression model. We assessed the relationship betweenIGF2BP2single nucleotide polymorphisms and the risk of breast cancer andclinic-pathological parameters and adjusted by age and BMI. p<0.05wasconsidered significantly difference.
Results:1.The average age of breast cancer patients was49.1±9.6yearsand48.1±9.9years in the control group of patients. The difference was notstatistically significant. The body mass index was25.5±3.6kg/m2in breastcancer patients and25.4±3.5kg/m2in normal control group, the differencebetween the two groups was statistically significant (P <0.001).
2. The frequencies of GT (43.3%), TT (6.2%), T genotype (GT+TT)(49.5%), and T allele (27.8%) were higher in cancer patients than thefrequencies of GT (36.5%), TT (3.6%), T genotype (40.1%), and T allele(21.8%) in the control groups. Women who were GT heterozygote (ORadj=1.442;95%CI,1.097-1.895) or TT homozygote (ORadj=2.0;95%CI,1.041–3.843), and carriers of T genotype (ORadj=1.494;95%CI,1.146–1.947)or T allele (ORadj=1.391;95%CI,1.120-1.727) were significantly associatedwith breast cancer risk.
3. Stratified analysis by age at diagnosis found that the total number ofage at diagnosis <50years was301in breast cancer patients, of which therewere134cases of rs4402960GT type,16cases of rs4402960TT type and150cases of rs4402960T genotype. The mutation rate was44.5%,5.3%and49.8%, respectively. The total number of age at diagnosis≥50years was263in breast cancer patients, of which there were110cases of rs4402960GT type,19cases of rs4402960TT type and129cases of rs4402960T genotype. Themutation rate was41.8%,7.2%and49%, respectively. The difference ofrs4402960mutation rate between two groups was not statistically significant(P>0.05).
4. Stratified analysis by menopausal status found that the total number ofpre-menopausal breast cancer patients was258, of which there were134casesof rs4402960GT type,12cases of rs4402960TT type and124cases ofrs4402960T allele genotype. The mutation rate was43.4%,4.7%and48.1%,respectively. The total number of post-menopausal breast cancer patients was278, of which there121cases of rs4402960GT type,21cases of rs4402960TT type and142cases of rs4402960T genotype. The mutation rate was43.5%,7.6%and51.1%, respectively. The difference of genotype distributionbetween the two groups was not statistically significant (P>0.05).
5. Stratified analysis by ER status showed that the total number of ERnegative breast cancer patients was179, of which there were71cases ofrs4402960GT type,11cases of rs4402960TT type and82cases of rs4402960T allele genotype. The mutation rate was39.7%,6.1%and45.8%, respectively.The total number of ER positive breast cancer patients was345, of whichthere were150cases of rs4402960GT type,20cases of rs4402960TT typeand170cases of rs4402960T genotype. The mutation rate was43.5%,5.8%and49.3%, respectively. The difference of genotype distribution between thetwo groups was not statistically significant (P>0.05).
6. Stratified analysis by PR status showed that the total number of PRnegative breast cancer patients was227, of which there were92cases ofrs4402960GT type,14cases of rs4402960TT type and106cases ofrs4402960T allele genotype. The mutation rate was40.5%,6.2%and46.7%,respectively. The total number of PR positive breast cancer patients was296,of which there were128cases of rs4402960GT type,17cases of rs4402960TT type and145cases of rs4402960T genotype. The mutation rate was43.2%,5.7%and49%, respectively. The difference of genotype distribution betweenthe two groups was not statistically significant (P>0.05).
7. Stratified analysis by HER-2status showed that the total number ofHER-2negative breast cancer patients was396, of which there were161casesof rs4402960GT type,26cases of rs4402960TT type and187cases ofrs4402960T genotype. The mutation rate was40.7%,6.6%and47.2%, respectively. The total number of HER-2positive breast cancer patients was123, of which there were59cases of rs4402960GT type,4cases of rs4402960TT type and63cases of rs4402960T genotype. The mutation rate was48%,3.3%and51.2%, respectively. The difference of genotype distributionbetween the two groups was not statistically significant (P>0.05).
8.Stratified analysis by P53status showed that the total number of P53negative breast cancer patients was118, of which there were48cases ofrs4402960GT type,5cases of rs4402960TT type and53cases of rs4402960T genotype. The mutation rate was40.7%,4.2%and44.9%, respectively. Thetotal number of P53positive breast cancer patients was327, of which therewere139cases of rs4402960GT type,20cases of rs4402960TT type and159cases of rs4402960T genotype. The mutation rate was42.5%,6.1%and48.6%, respectively. The difference of genotype distribution between the twogroups was not statistically significant (P>0.05).
9. Stratified analysis by Ki-67status showed that the total number ofKi-67negative breast cancer patients was84, of which there were39cases ofrs4402960GT type,2cases of rs4402960TT type and41cases of rs4402960T genotype. The mutation rate was46.4%,2.4%and48.8%, respectively. Thetotal number of Ki-67positive breast cancer patients was379, of which therewere155cases of rs4402960GT type,24cases of rs4402960TT type and179cases of rs4402960T genotype. The mutation rate was40.9%,6.3%and47.2%, respectively. The difference of genotype distribution between the twogroups was not statistically significant (P>0.05).
10. Stratified analysis by lymph node metastasis showed that the totalnumber of breast cancer patients without lymph node metastasis was251, ofwhich there were106cases of rs4402960GT type,17cases of rs4402960TTtype and123cases of rs4402960T genotype. The mutation rate was42.2%,6.8%and49%, respectively. The total number of breast cancer patients withlymph node metastasis was255, of which there were109cases of rs4402960GT type,15cases of rs4402960TT type and124cases of rs4402960Tgenotype. The mutation rate was42.7%,5.9%and48.6%, respectively. The difference of genotype distribution between the two groups was notstatistically significant (P>0.05).
11. Stratified analysis by tumor size showed that the total number ofbreast cancer patients whose tumor diameter≤2cm was248, of which therewere100cases of rs4402960GT type,15cases of rs4402960TT type and115cases of rs4402960T genotype. The mutation rate was40.3%,6%and46.4%,respectively. The total number of breast cancer patients whose tumordiameter>2cm was234, of which there were111cases of rs4402960GT type,14cases of rs4402960TT type and125cases of rs4402960T genotype. Themutation rate was47.4%,6%and53.4%, respectively. The difference ofgenotype distribution between the two groups was not statistically significant(P>0.05).
12. Stratified analysis by histological grade showed that the total numberof histological grade of Ⅰ-Ⅱ breast cancer patients was349, of which therewere141cases of rs4402960GT type,17cases of rs4402960TT type and158cases of rs4402960T genotype. The mutation rate was40.4%,4.9%and45.3%, respectively. The total number of histological grade of Ⅲ breastcancer patients was46, of which there were18cases of rs4402960GT type,5cases of rs4402960TT type and23cases of rs4402960T genotype. Themutation rate was39.1%,10.9%and50%, respectively. The difference ofgenotype distribution between the two groups was not statistically significant(P>0.05).
13. Stratified analysis by tumor clinical staging showed that the totalnumber of stageⅠbreast cancer patients was155, of which there were60cases of rs4402960GT type,11cases of rs4402960TT type and71cases ofrs4402960T genotype. The mutation rate was38.7%,7.1%and45.8%,respectively. The total number of stage Ⅱ breast cancer patients was215, ofwhich there were88cases of rs4402960GT type,10cases of rs4402960TTtype and98cases of rs4402960T genotype. The mutation rate was40.9%,4.7%and45.6%, respectively. The total number of stage Ⅲ breast cancerpatients was156, of which there were76cases of rs4402960GT type,11 cases of rs4402960TT type and87cases of rs4402960T genotype. Themutation rate was48.7%,7.1%and55.8%, respectively. The total number ofstage Ⅳbreast cancer patients was38, of which there were20cases ofrs4402960GT type,3cases of rs4402960TT type and23cases of rs4402960T genotype. The mutation rate was52.6%,7.9%and60.5%, respectively. Thedifference of genotype distribution between the two groups was notstatistically significant (P>0.05).
14. Stratified analysis by molecular typing showed that the total numberof Luminal A type breast cancer patients was74, of which there were33casesof rs4402960GT type,2cases of rs4402960TT type and35cases ofrs4402960T genotype. The mutation rate was44.6%,2.7%and47.3%,respectively. The total number of Luminal B type breast cancer patients was254, of which there were108cases of rs4402960GT type,16cases ofrs4402960TT type and124cases of rs4402960T genotype. The mutation ratewas42.5%,6.3%and48.8%, respectively. The total number of ERBB2+typebreast cancer patients was66, of which there were30cases of rs4402960GTtype,2cases of rs4402960TT type and32cases of rs4402960T genotype.The mutation rate was45.5%,3%and48.5%, respectively. The total numberof Basal-like type breast cancer patients was93, of which there were35casesof rs4402960GT type,6cases of rs4402960TT type and41cases ofrs4402960T genotype. The mutation rate was37.6%,6.5%and44.1%,respectively. The difference of genotype distribution between the two groupswas not statistically significant (P>0.05).
Conclusions:1.There was no significant difference between the age ofbreast cancer patients and normal control cases. BMI of breast cancer patientswas higher than which of the control cases, suggesting that BMI is a riskfactor for breast cancer disease. Normal people should pay attention to dietand exercise to reduce BMI, thereby reducing the risk of breast cancer.
2. There was significant relationship between the IGF2BP2geners4402960polymorphism and risk of breast cancer. The frequencies adjustedby age and BMI of T genotype (GT+TT)(ORadj=1.494,95%CI=1.146-1.947) and T allele (ORadj=1.391,95%CI=1.120-1.727) were significantlyincreased the risk of breast cancer. But there was no association betweenIGF2BP2gene rs4402960polymorphism and age at diagnosis, lymph nodemetastasis, estrogen receptor, progesterone receptor, HER-2receptor status,P53, Ki-67status, tumor size, histological grade, tumor clinical stage andmolecular typing.
引文
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