DNA修复通路基因复合突变对遗传性乳腺癌-卵巢癌综合征中表型扩展的作用与机制研究

The hereditary breast and ovarian cancer (HBOC) syndrome is characterized by multiple cases of breast cancer and/or ovarian cancer in the family, accounting for 5-10% of all breast cancers. The main cause of HBOC is the pathogenic mutation in BRCA1/2 genes. Sometimes, HBOC complicates with non-HBOC tumor such as lung cancer and liver cancer as the "phenotype expansion", whose genetic etiology is still unclear. Therefore, there is no effective prediction method and treatment basis for the phenotype expansion in HBOC. Based on our previous study, we found the surprising phenomenon that compound variants in DNA repair pathway existed in a HBOC pedigree with phenotype expansion. Furthermore, we hypothesized that ‘compound variants in DNA repair pathway may contribute to the occurrence of phenotype expansion of HBOC’. In this project, we aim to verify the pathogenicity of the compound inheritance model by the genome-edited mouse model using the CRISPR-Cas9 system. This will provide theoretical foundation of genetic and molecular etiology for phenotype expansion of HBOC, and a new clinical and genetics classification of HBOC will also be explored.

遗传性乳腺癌-卵巢癌（Hereditary breast and ovarian cancer, HBOC）综合征占全部乳腺癌的5-10%，以家族中多发乳腺癌和卵巢癌为临床特征，其主要病因为BRCA1/2突变，目前已有针对性的筛查和诊疗手段。然而，HBOC常出现“表型扩展”，即合并肺癌和肝癌等非HBOC肿瘤，难以用BRCA1/2突变解释表型全貌，因而缺乏有效的预测手段和治疗依据。申请人基于前期在HBOC家系中发现表型扩展的患者携带BRCA2与RECQL双突变的独特现象，并通过乳腺癌疾病队列证实DNA通路复合突变与HBOC表型扩展相关，进而提出“DNA修复通路复合突变是HBOC中表型扩展的重要遗传学病因”的科学假说。拟通过CRISPR/Cas9构建DNA修复通路复合突变小鼠模型，从动物与细胞水平探索DNA修复通路复合突变对HBOC表型扩展的致病机制，为预测疾病发展和探寻治疗靶点提供理论依据。

遗传性乳腺癌-卵巢癌（Hereditary breast and ovarian cancer, HBOC）综合征占全部乳腺癌的5-10%，以家族中多发乳腺癌和卵巢癌为临床特征，其主要病因为BRCA1/2突变，目前已有针对性的筛查和诊疗手段。然而，HBOC常出现“表型扩展”，即合并肺癌和肝癌等非HBOC肿瘤，提示DNA修复通路可能存在剂量效应。为证实该科学假说，申请人构建了乳腺特异性Brca1条件性敲除和Brca2全身敲除的小鼠模型，构建DNA修复通路剂量深度缺陷的小鼠模型，证实Brca1乳腺特异性纯合敲除联合Brca2全身杂合敲除小鼠能够在平均33周发生乳腺癌，显著早于既往报道的Brca1乳腺特异性纯合敲除小鼠（40周+）。进一步，对DNA修复通路缺陷型乳腺癌进行基因型和表型关联研究，通过对3041名乳腺癌患者进行DNA修复通路基因测序，发现11.3%患者存在基因突变，其中以BRCA1/2基因为主。表型分析提示DNA修复通路缺陷型乳腺癌具有高度一致的表型，包括更早的发病年龄、阳性家族史和特征病理。进一步，我们通过基因型表型关联研究和神经网络，建立了基于表型的DNA修复通路缺陷型乳腺癌预测模型，准确性超过目前国际常用模型。本研究在临床队列和动物模型两个层面，证实了DNA修复通路缺陷型乳腺癌基因型和表型的对应关系，并存在剂量效应，为预测疾病发展和探寻治疗靶点提供理论依据。

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