着色性干皮病基因A多态性与乳腺癌易感性的关联研究

Breast cancer is a leading cause of cancer mortality with an inter-individual difference in susceptibility to the disease. The inheritance of low-efficiency genotypes involved in nucleotide excision repair may contribute to the difference in susceptibility. We evaluated whether the breast cancer risk was influenced by the single nucleotide (-4) G/A polymorphism in xeroderma pigmentosum group A (XPA), which codes for an essential protein in NER. Our study included 300 sporadic breast cancer cases and 100 hereditary breast cancer cases and 400 age-matched cancer free controls. The genotypes of the XPA -4G/A polymorphism were determined by real-time PCR. The same population was also characterised for BRCA1/2 variant to search for possible functional interactions XPA -4G/A polymorphism and other susceptibility genes. The participants were interviewed either in person or by phone using epidemiology and family history questionnaires that collect information on age, reproductive history, hormone use and physical activity. In our study, we screened the XPA -4G/A polymorphism in sporadic breast cancer without any family history of breast cancer and hereditary breast cancer. Multivariate logistic regression analysis was performed to reveal the susceptibiltiy to breast cancer in individuals carrying the XPA -4G/A polymorphism. And Subgroup analyses were performed by sporadic breast cancer or hereditary breast cancer and family history with BRCA1/2 status (family history with non-BRCA1/2 cases and family history with BRCA1/2-positive cases). And we also examined gene-environment interactions in relation to breast cancer in individuals recruited.

乳腺癌是我国女性最常见的恶性肿瘤，本研究拟通过以300例散发性乳腺癌患者及100例家族性乳腺癌患者为研究对象，对核苷酸切除修复途径中识别DNA损伤的着色性干皮病基因A单核甘酸多态性位点进行病例对照的关联分析和研究。采用荧光定量PCR技术检测XPA -4G/A基因多态性，确定我国人群中乳腺癌患者的基因型分布，同时，对乳腺癌相关基因BRCA1/2的突变情况进行分析，结合发病年龄及婚育史等因素，研究XPA -4G/A基因多态性与乳腺癌易感性之间的联系，综合评价该基因多态性对乳腺癌易感性的影响；并通过比较散发性乳腺癌和家族性乳腺癌的易感性程度，为乳腺癌高危人群筛查和针对病因制定预防措施提供科学依据。

乳腺癌是我国女性最常见的恶性肿瘤，且其发病风险存在易感性的差异。本研究针对核苷酸切除修复途径中识别DNA损伤的着色性干皮病基因A -4G/A多态性和乳腺癌发病风险，通过收集乳腺癌患者外周血样本，首先确立我国人群中该多态性位点基因型的分布频率，根据最小等位基因概率确定野生型基因型AA。然后结合发病年龄等通过聚合酶链反应-限制性片段长度多态性分析乳腺癌和对照组两组人群XPA -4G/A多态性分布，同时应用Logistic回归方法计算其多态性与乳腺癌发病风险的关联强度，综合评价XPA -4G/A基因多态性对乳腺癌易感性的影响。通过研究我们发现，G/G基因型在乳腺癌病例中的基因型分布频率要低于对照组。通过等位基因模型比较后发现等位基因G的携带者在健康人群中出现的频率更高，同时，在针对纯合子G/G基因型的比较中，也发现了AA+AG/GG的频率分布在乳腺癌组和对照组中接近统计学显著差异的临界值，因此提示XPA -4G等位基因携带者有可能反而会降低其发生乳腺癌的风险。同时，我们也收集了部分乳腺癌术后组织标本，针对瞬时受体电位通道M型(TRPM)过度表达与乳腺癌的转移与否进行了关联分析。通过Western Blot等方法分别在mRNA、蛋白表达水平检测TRPM8在乳腺癌组织与癌旁组织之间的表达差异，以及正常乳腺上皮细胞株MCF-10A以及不同转移能力乳腺癌细胞株TRPM8的表达差异，研究发现癌旁组织标本TRPM8表达量均较低，且正常乳腺上皮细胞株MCF-10A相对于其他六种具有转移能力的乳腺癌细胞的TRPM8相对表达水平最低，初步得出乳腺癌细胞中TRPM8的mRNA及蛋白相对表达量的高低与其细胞侵袭、转移能力可能有关，即细胞中的TRPM8相对表达量越高，其侵袭、转移能力越强，从而试图为乳腺癌的筛查预防和治疗提供实验依据。