中国人群特异BRCA1/2重复突变的乳腺癌发病风险评估及功能研究

Our previous work showed that the cumulative risk of breast cancer in BRCA1 /2 mutation carriers in Chinese women is lower than that in Caucasian women. Breast cancer risk varied by type and location of BRCA1/2 mutation. Approximately 50% of BRCA1/2 mutations were Chinese specific mutations, including some high frequency recurrent mutations. Therefore, the aim of this study was to investigate the breast cancer risk in Chinese women who carry a recurrent BRCA1/2 mutation, and to find out the mechanism of these recurrent mutations affecting the function of BRCA1/2. In the current study, we will detect these recurrent mutations and collect the pedigree data, identify the recurrent mutations with higher breast cancer risk in Chinese women, and investigate whether these high risk recurrent mutations affect the function of BRCA1/2 through homologous recombination assay. It would be helpful for efficiently screening high-risk women in the population level, and provide individual genetic counseling and clinical recommendations.

我们的近期研究显示：中国健康女性BRCA1/2基因突变携带者的乳腺癌发病风险低于高加索白人，相关原因不明。业已证实乳腺癌发病风险受BRCA1/2突变类型和突变位置的影响。我们前期工作表明，大约50%的BRCA1/2突变是中国人群特异的，包括一些特异的高频重复突变。本研究探索这些中国人群特异重复突变的乳腺癌发病风险及相关机制。基于此，本课题将对完成BRCA1/2基因突变检测的大宗乳腺癌患者进行家族史问卷调查，并结合乳腺癌患者个人信息、临床病理资料及家系信息，明确这些中国人群特异BRCA1/2基因重复突变的乳腺癌发病风险，筛选出其中风险较高的重复突变，并用同源重组实验的方法探索重复突变对BRCA1/2功能的影响。本研究将有利于在人群中快速的定点检测出高风险人群，提供更个体化的精准遗传咨询和临床建议。

BRCA1/2基因胚系突变与乳腺癌的发生密切相关。BRCA1/2基因突变谱具有种族特异性。我们前期工作中发现的约50%的BRCA1/2突变为中国人群特异性的突变，其中不乏高频突变。但这些高频突变是否是中国人特异的始祖突变，高频重复突变对应的乳腺癌发病风险是多少，高频重复突变是否与BRCA1/2基因功能相关，与乳腺癌的临床病理表型是否相关，这一系列问题始终是目前研究的空白。.在中国汉族9505例乳腺癌患者中用二代和/或一代测序发现25种发生频率在4人次以上的重复突变。经单倍体型分析后发现在中国人群中发生频率最高的BRCA1 c.5470_5477del突变是中国人特异的高频始祖突变，BRCA1 c.3359_3363del、BRCA1 c.5521del、BRCA2 3109 C>T也具有中国人始祖突变的可能性。.在3984个家系中明确了BRCA1/2基因状态，通过家系分析、Kaplan-Meier、Cox回归及Kin-cohort等方法发现中国健康女性BRCA1突变携带者至80岁时发生乳腺的累积风险是45.4%；BRCA2突变携带者的风险是41.6% 。中国健康女性BRCA1/2突变携带者发生乳腺癌的风险是普通人群的8倍。.中国人群始祖突变BRCA1 c.5470_5477del突变携带者到70岁时发生乳腺的累积风险即已达到37.9% (95%CI 18.3%-80.4%)。这可能与其在BRCA1基因BRCT domain相关。中国健康女性携带发生在BRCA1基因BRCT domain的突变会导致在80岁时发生乳腺的累积风险是63% (95%CI 39.4%-83.1%)，显著高于包括BRCA1 c.3359_3363del、BRCA2 3109 C>T在内的发生在BRCA1基因中部的突变相关的风险。且一旦罹患乳腺癌，携带BRCA1 c.5470_5477del突变的乳腺癌患者预后较非携带者显著差（无病生存, p = 0.049; 总生存, p = 0.029），具有较强的恶性表型。.本研究表明，高频中国始祖突变BRCA1 c.5470_5477del与较高的乳腺癌发病风险相关，且一旦携带者发病，其预后较差。故精准遗传咨询中，基因突变的具体位点是不容忽视的与发病风险及预后相关的因子。

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