中国家族性乳腺癌BRCA1/2基因大片段重排断裂位点鉴定及功能研究

大片段重排是BRCA1/2基因致病性突变方式之一，无法被常规的Sanger测序检测到。可靠的大片段重排突变的检测方法是多重连接依赖探针扩增技术(Multiplex Ligation-Dependent Probe Amplification, MLPA)。目前中国家族性乳腺癌患者BRCA1/2基因大片段重排突变仅有小样本报道。我们前期用MLPA方法检测了321例Sanger检测BRCA1/2阴性的中国家族性乳腺癌的大片段重排突变，发现其突变频率高达3.7%。本研究拟纳入1000例中国汉族家族性乳腺患者，对Sanger检测为阴性的患者进行MLPA的检测，明确我国家族性乳腺癌患者BRCA1/2基因大片段重排突变的频率、突变谱，以及与临床表型的相关性。本研究还将重点鉴定重排突变的断裂位点，探索大片段重排的发生机制及对BRCA1/2功能的影响，为大片段重排突变患者的预防和治疗提供理论依据。

A substantial of BRCA1/2 germline mutations may be due to large genomic rearrangements (LGRs), which cannot be detected by using routine Sanger-sequencing assay. Multiplex Ligation-Dependent Probe Amplification (MLPA) assay is the most common and effective method for detecting LGRs. To data, few studies have investigated BRCA1/2 large rearrangements in Chinese women with familial breast cancer. We recently found that the prevalence of BRCA1/2 LGRs is 3.7% in 321 Chinese familial breast cancer patients who were negative for BRCA1/2 Sanger sequencing. In this study, 1000 Chinese women with familial breast cancer are involved, we first investigate the prevalence and pattern of LGRs in those who are negative for BRCA1/2 Sanger sequencing, and further explore the association between BRCA1/2 LGRs and clinical phenotype. We then identify break points of BRCA1/2 LGRs and investigate the underlying mechanism and functional characteristic of BRCA1/2 LGRs. This study may be useful for improving the screening and treatment strategies for Chinese familial breast cancer patients who carry a large rearrangement mutation in BRCA1/2.