早发性乳腺癌与锌指蛋白350基因多态性的关系

Association between zinc finger protein 350 gene polymorphism and early onset breast cancer among women from different ethnic groups in Xinjiang

目的检测新疆地区妇女早发性乳腺癌锌指蛋白350(ZNF350)基因外显子突变,探讨其多态性(SNP)与早发性乳腺癌的相关性.方法直接测序法检测新疆地区汉族、少数民族妇女早发性乳腺癌(年龄范围为30 ~ 40岁,各80例)ZNF350基因外显子区域的突变,采用Polyphen和SIFT软件预测突变对蛋白质功能的影响,并用x^2检验计算P值、相对危险度(OR)和95%可信区间(CI),分析多态性位点基因型分布与临床病理特征的相关性.结果(1) ZNF350基因外显子区域突变检测结果:共检测出9个突变位点(实验前参照数据库最小等位基因频率MAF均>1%),包括5个错义突变和4个同义突变,分别位于EXON3、EXON4和EXON5.其中,少数民族人群中检测到8个位点突变,汉族有7个位点突变,均包括4个错义突变.(2) Polyphen和SIFT软件预测蛋白质功能:结果表明少数民族、汉族早发性乳腺癌患者共有的突变位点rs4987241、rs2278415均为有害突变,可能影响ZNF350蛋白质的功能.(3)多态性位点基因型分布与临床病理特征的相关性:①rs4986773与少数民族乳腺癌腋窝淋巴结状态明显相关(r=0.234,P<0.05),突变型可增加腋窝淋巴结转移风险.②rs2278420、rs2278415、rs4988334、rs3764538与汉族乳腺癌腋窝淋巴结状态明显相关(r=-0.240、-0.240、-0.200、-0.200,P<0.05),突变型均可降低腋窝淋巴结转移风险.③rs2278420、rs2278415、rs4986773、rs4988334、rs3764538在少数民族三阴性与非三阴性乳腺癌组间分布明显相关(r=0.234、0.234、0.221、0.245、-0.245,P<0.05),rs3764538突变型可降低少数民族乳腺癌患者中三阴性亚型发病风险,其余4个位点突变型均可增加此风险.④rs4987241、rs4988334、rs3764538与肿瘤大小明显相关(r=0.500、-0.306、-0.339,P<0.05),rs4987241突变型可显著增加汉族乳腺癌患者肿瘤直径的风险,而rs4988334、rs3764538突变型则降低此风险.⑤rs4986773、rs4988334基因型分布均与汉族乳腺癌初潮年龄明显相关(r=0.234、0.234,P<0.05),初潮年龄≥14岁的乳腺癌患者突变型携带率等于或高于初潮年龄< 14岁的乳腺癌患者.⑥rs4986771、rs138898320、rs4986772位点基因型分布与临床病理特征均无相关性(P>0.05).结论在新疆地区早发性乳腺癌中,ZNF350基因多态性与初潮年龄、肿瘤大小、腋窝淋巴结转移状况、三阴性乳腺癌明显相关.

Objective To detect the variants of zinc finger protein 350 (ZNF350) gene in exon of Xinjiang women with early onset breast cancer, and investigate the relationship between Polymorphism and the early onset breast cancer of women. MethodsExon region of ZNF350 gene are detected via direct sequencing in Xinjiang minority and Han nationality women with early onset breast cancer (age: 30-40 years old, separately 80 cases), The impact of Non-synonymous variants on protein function are predicted by using Polyphen and SIFT software, and then analyzing the relationship between Polymorphism genotypes and clinical pathological features. Results(1) The test results of ZNF350 gene exon region mutation: Nine mutations are detected (referring to database minimum allele frequency MAF>1% before the trial), including 5 missense mutations and 4 synonymous mutations, which located in EXON3, EXON4 and EXON5. Among them, the Uighur nationality are detected eight locus mutations, and the han nationality have seven locus mutations, which including 4 missense mutations respectively.(2) Using Polyphen and SIFT software to predict protein function: The result show that the common mutation sites rs4987241 and rs2278415 of minority and Han nationality patients with early-onset breast cancer are deleterious mutations, which may affect the ZNF350 protein function.(3) The relevance between distribution of polymorphic genotype and clinical pathological features:① There is a certain correlation between rs4986773 and axillary lymph node status of breast cancer in minority (r=0.234, P<0.05), and the mutant can increase the risk of axillary lymph node metastasis.② There is a certain correlation between the mutation sites (rs2278420, rs2278415, rs4988334 and rs3764538) and axillary lymph node status of han nationality with breast cancer (r=-0.240,-0.240,-0.240,-0.240, P<0.05), and the mutants may reduce the risk of axillary lymph node metastases.③ There are differences in rs2278420, rs2278415, rs4986773, rs4988334 and rs3764538 among triple negative and non-triple negative breast cancer in minority group (r=0.234, 0.234, 0.221, 0.245,-0.245, P<0.05), and rs3764538 mutant can reduce the breast cancer patients, risk of triple-negative subtype in minority, The other four locus mutations can increase this risk.④ There is a certain correlation between the mutation sites (rs4987241, rs4988334 and rs3764538) and the tumor size (r=0.500,-0.306,-0.339, P<0.05), and rs4987241 mutant can significantly increase the risk of breast cancer tumor diameter of Han nationality, While rs4988334 and rs3764538 mutants can reduce the risk.⑤ rs4986773, rs4988334 genotypes are associated with menarche age of breast cancer in Han nationality (r=0.234, 0.234, P<0.05). The mutant carrying rate in Menarche age at ≥14 of breast cancer patients is equal or higher than the menarche age at<14 years of breast cancer patients.⑥ There are no significant differences in rs4986771, rs138898320 and rs4986772 site genotype distribution with clinical pathologic characteristics (P>0.05). Conclusion Among early-onset breast cancer in Xinjiang women, there is a certain correlation between ZNF350 gene polymorphism and menarche age, tumor size, axillary lymph node status and triple-negative breast cancer, which can be used as one of the predictors to guide the early-onset breast cancer individualize treatment in Xinjiang women.