中度风险易感基因CHEK2,PALB2,CDH1筛查在多民族地区BRCA1/2突变阴性遗传性乳腺癌中的作用

Compared with Han ethnic group, breast cancer patients in Urgur ethnic group manifest different features such as onset age and histopathological feature.To date, up to 5-10% of all breast cancers are caused by germline mutations in well -identified breast cancer susceptibility genes.The high-risk breast cancer susceptibility genes include BRCA1 and BRCA2. Our previous studies indicated that the frequency of BRCA mutation of patients with hereditary disposition to breast cancer in Xinjiang were only 12% and the spectrum of BRCA mutation in Xinjiang is different compared with that in other regions in china. It is plausible to screen moderate risk susceptibility gene such as CHEK2,PALB2 and CDH1 among non BRCA1/BRCA2 mutation patients with hereditary disposition to breast cancer. The main purpose of this study is to investigate mutaiton profile of CHEK2,PALB2 and CDH1 in patients with hereditary breast cancer disposition between Han and Urgur ethnic group and different risk factors between two ethnic groups and to specify clinicopathological features relevant to interactions between CHEK2, PALB2 and CDH1 mutation and enviormental risk factors in different ethnic groups. It aims to validate effects of interaction between genetic mutation and risk factors on hereditary breast cancer in multiple ethnic group region in china and develop the genetic testing strategy in high risk population and risk management in multiple ethnic group region in china.

与汉族相比，维吾尔族乳腺癌在发病年龄及组织病理方面有其明显不同特点。遗传性乳腺癌约占乳腺癌的5%-10%。BRCA1和BRCA2是遗传性乳腺癌两个主要高风险易感基因。本项目前期结果表明：BRCA突变仅占遗传倾向乳腺癌12%，新疆地区遗传性乳腺癌BRCA突变谱与内地不同。故有必要研究中度风险易感基因CHEK2,PALB2及CDH1基因在新疆地区BRCA突变阴性的遗传倾向乳腺癌中的作用。本研究通过了解维吾尔族和汉族生活习惯的差异及CHEK2,PALB2 及CDH1 基因突变谱在维、汉族遗传性乳腺癌的分布特点，明确维吾尔族遗传性乳腺癌的发病特点与CHEK2，PALB2及CDH1基因突变、环境因素的相关性：证实基因突变与环境因素（生活、饮食习惯）交互作用对不同民族遗传性乳腺癌发生发展的影响，为多民族地区遗传性乳腺癌高危人群筛查，早期诊断、风险评估提供依据及新途径。

在新疆地区，维吾尔族乳腺癌与汉族相比在发病年龄及组织病理方面有其明显不同特点。本项目前期结果表明：BRCA突变仅占遗传倾向乳腺癌12%，新疆地区遗传性乳腺癌BRCA突变谱与内地不同，因此本项目研究中度风险易感基因CHEK2,PALB2及CDH1基因在新疆地区BRCA突变阴性的遗传倾向乳腺癌中的作用。对267例有遗传风险乳腺癌标本进行了BRCA1、BRCA2、PALB2、CHEK2、CDH1基因突变进行二代检测。（仅BRCA1、BRCA2、PALB2基因检测到致病性突变）BRCA1突变32（17+15）例，突变率11.98%（32/267），BRCA2突变28（16+12）例，突变率10.49%（28/267）。与西方BRCA1 突变率及突变占据BRCA突变主导作用不同，中国BRCA2突变率及作用至少不低于BRCA1。112例BRCA1/2突变阴性的乳腺癌患者，PALB2突变6（4+2）例，突变率2.25%（6/267），行CHEK2,CDH1基因突变筛查，未检测出致病性突变，致病性突变检出率为0%（0/112）。仅检测到3例CHEK2错义突变及2例CDH1错义突变。其临床意义未明。267例新疆患者中，除外BRCA1/2致病性突变及错义突变患者后，有112例患者为BRCA1/2突变阴性患者。PALB2基因编码的蛋白可与 BRCA2 结合共同定位于细胞核内聚集点（nuclear foci）, 它作为协同因子在BRCA2 向细胞核内转移、定位和稳定累积中, 同时它也与 BRCA1相互作用, 从而将 BRCA1 和 BRCA2的 DNA 损伤修复功能相联系。新疆地区中度遗传风险乳腺癌PALB2基因突变增加了乳腺癌的发病风险,对BRCA1/2突变阴性的乳腺癌建议继续进行PALB2基因突变检测。