卵巢上皮性癌患者外周血BARD1基因单核苷酸多态性与BRCA1基因突变风险的关系

Association between single nucleotide polymorphism of BARD1 gene and BRCA1 gene mutation in epithelial ovarian cancer

目的探讨BARD1基因Val507Met、Arg378Ser及Pro24Ser位点单核苷酸多态性（SNP）与卵巢上皮性癌（卵巢癌）BRCA1基因突变风险的关系。方法收集2016年1-10月郑州大学附属肿瘤医院经第2代基因测序（NGS）技术检测明确为BRCA1基因突变的卵巢癌患者19例及BRCA1基因未突变的卵巢癌患者50例，所有患者均经病理检查确诊。（1）采用第2代基因测序（NGS）技术检测69例卵巢癌患者外周血BARD1基因的突变情况。（2）采用Pearson线性相关分析法对卵巢癌患者BARD1基因不同突变位点之间基因型改变的相关性进行分析。（3）采用非条件logistic回归法分析卵巢癌患者携带BARD1基因各突变位点其不同基因型的BRCA1基因突变风险。（4）采用χ^2检验或Fisher精确概率法对不同临床病理特征的卵巢癌患者其携带BARD1基因Val507Met、Arg378Ser及Pro24Ser位点不同基因型后的BRCA1基因突变风险进行分析。结果（1）NGS技术检测显示，69例卵巢癌患者共发现8个BARD1基因突变位点，其中Val507Met、Arg378Ser及Pro24Ser为最常见的基因突变位点，其突变率均为54％（37／69）。（2）Pearson线性相关分析显示，Val507Met与Arg378Ser位点（r=0．929，P〈0.01）、Val507Met与Pro24Ser位点（r=0．801，P〈0.01）、Arg378Ser与Pro24Ser位点（r=0．748，P〈0．01）之间的基因型改变均呈明显正相关。（3）携带BARD1基因的Val507Met位点AA基因型、Arg378Ser位点CC基因型、Pro24Ser位点TT基因型的卵巢癌患者的BRCA1基因突变风险明显增高（P〈0．05）。（4）携带BARD1基因各突变位点不同基因型，即Val507Met（GG、AA＋GA）、Arg378Ser（GG、CC＋GC）及Pro24Ser（CC、TT＋CT）位点基因型与卵巢癌患者年龄、家族史、绝经与否、输卵管结扎史以及铂类药物敏感性无明显关系（P〉0.05）；但其均与BRCA1基因突变明显有关（P〈0．05）。进一步分析显示，Val507Met及Arg378Ser位点发生BRCA1基因突变的风险在发病年龄早（≤60岁）、无家族史、已绝经、无输卵管结扎史及对铂类药物敏感的卵巢癌患者中更为明显（P〈0.05），而Pro24Ser位点发生BRCA1基因突变的风险仅在已绝经的卵巢癌患者中更为明显（P〈0．05）。结论BARD1基因Val507Met、Arg378Ser及Pro24Ser位点为卵巢癌中最常见的突变位点，其与BtlCA1基因的突变风险有关，而这种风险与患者年龄、家族史、绝经与否、输卵管结扎史、铂类药物敏感性等明显相关。

Objective To investigate the relationship between single nucleotide polymorphism （SNP） of BARD1 gene and BRCA1 gene in epithelial ovarian cancer （EOC）. Methods Nineteen EOC patients with BRCA1 gene mutation and 50 EOC cases without BRCA1 gene mutation between January 2016 and October 2016 were collected, and all EOC were diagnosed by pathological method. BARD1 gene variants were detected by next generation sequencing （NGS）. The SNP of BARD1 gene was analyzed by Pearson linear correlation. Logistic regression analysis was used to research the clinicopathologic features and BRCA1 gene mutation associated with BARD1 gene SNP. Pearson＇s chi-square test was used to analyze the association between BARD1 gene Val507Met, Arg378Ser and Pro24Ser with different clinicopathologic features and BRCA1 gene mutation risk. Results （1） Eight BARD1 gene variants were found in 69 ovarian cancer patients, in which Val507Met, Arg378Ser and Pro24Ser were common variants, and the rate of mutation were all 54% （37/69）. （2） There was a significant linear correlation among Val507Met, Arg378Ser and Pro24Ser （all P〈O.01）. （3） Obvious difterences were found in Val507Met, Arg378Ser and Pro24Ser of BARD1 gene between BRCA1 ＋ and BRCAI-（all P〈0.05）. （4） No differences were found between BARD1 gene Val507Met, Arg378Ser and Pro24Ser and the clinieopathologic features （all P〉0.05）, while obvious differences were found in BRCA1 gene mutation compared to the controls group. The risk of BRCA1 mutation in Val507Met and Arg378Ser were more evident in subjects with negative family history, positive menopause history, negative tubal ligation, onset age （≤60 years old） and sensitivity to platinum-based chemotherapy in EOC （all P〈0.05）, while Pro24Ser was only more evident in positive menopause history of EOC （P〈0.05）. Conclusions BARD1 Val507Met, Arg378Ser and Pro24Ser are the common genotypes, which are associated with BRCAI mutation in EOC. The family history, menopause history, tubal ligation, onset age and sensitivity to platinum-based chemotherapy have effects on BARD1 SNP in the risk of BRCA1 gene mutation.