筛选肿瘤易感基因有助于识别用于家族性癌症监测、预防和诊断的强效生物标志物，为了解家族性癌症综合征的潜在分子机制和生物标志物提供了机会，而这有助于精准治疗家族性癌症综合征。对血液进行全外显子测序和生物信息学分析发现在一个患有家族性癌症综合征的家庭中发现了一个新的RBBP8（p.E281*）胚系突变，通过Sanger测序进行了验证。通过CCK-8、胚营养实验、Transwell和活体异种移植实验研究了细胞增殖、培养大肠杆菌的能力、细胞迁移和体内肿瘤生成。通过免疫荧光、核和胞浆蛋白提取试剂盒和Co-IP检测了蛋白质的定位和相互作用。发现了RBBP8（p.E281*）基因的新的杂合胚系突变与家族性遗传性癌症综合征相关。RBBP8-WT主要存在于细胞核并与BRCA1发生相互作用。相比之下，RBBP8（p.E281*）主要位于细胞质中，与BRCA1没有相互作用。RBBP8（p.E281*）的变异在细胞质中除了核内丧失功能外还发挥着致癌作用，这会促进乳腺癌的增殖、体内肿瘤生成和迁移。与对照组相比，RBBP8（p.E281*）对顺铂和奥拉帕尼处理显示出升高的细胞死亡率。从家族性遗传性癌症综合征中鉴定了一个新的RBBP8（p.E281*）胚系突变。由于丧失了结合位点，RBBP8（p.E281*）无法进入细胞核或与BRCA1发生相互作用，而RBBP8（p.E281*）变异似乎除了核内失去功能外，还在细胞质中促进了肿瘤发生。RBBP8（p.E281*）变异可能促进肿瘤易感性，同时作为家族性遗传性癌症综合征的精确医学生物标志物。重要信息：RBBP8（p.E281*）是家族性遗传性癌症综合征中的易感基因。RBBP8（p.E281*）失去了进入细胞核和BRCA1结合位点的能力。新的RBBP8（p.E281*）胚系突变促进了乳腺癌的肿瘤发生。携带RBBP8（p.E281*）胚系突变的患者可能从奥拉帕尼和顺铂中获益。© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Screening tumor susceptibility genes helps in identifying powerful biomarkers for hereditary cancer monitoring, prevention, and diagnosis, providing opportunities for understanding potential molecular mechanisms and biomarkers for the precise treatment of hereditary cancer syndromes. Whole-exome sequencing of blood and bioinformatics analysis uncovered a novel RBBP8(p.E281*) germline mutation in a family with hereditary cancer syndrome, which was verified by Sanger sequencing. Cell proliferation, colony formation, cell migration, and in vivo tumorigenesis were investigated by CCK8, colony formation, Transwell, and in vivo xenograft assays. Protein localization and interaction were detected by immunofluorescence, nuclear and cytoplasmic protein extraction kits, and Co-IP. A new heterozygous germline mutation of the RBBP8(p.E281*) gene was found to be associated with familial hereditary cancer syndrome. RBBP8-WT was mainly detected in the nucleus and interacts with BRCA1. In contrast, RBBP8(p.E281*) is mainly located in the cytoplasm, with no interaction with BRCA1. RBBP8(p.E281*) variant plays an oncogenic role in the cytoplasm in addition to its loss of function in the nucleus, which promotes breast cancer proliferation, in vivo tumorigenesis, and migration. Compared with the control group, RBBP8(p.E281*) showed elevated cell death in response to cisplatin and olaparib treatment. A novel RBBP8(p.E281*) germline mutation was identified from familial hereditary cancer syndrome. RBBP8(p.E281*) is not able to enter the nucleus or interact with BRCA1 through the lost binding motif, and RBBP8(p.E281*) variant appears to promote tumorigenesis in the cytoplasm in addition to its loss of function in the nucleus. RBBP8(p.E281*) variant may promote tumor susceptibility and serve as a precision medicine biomarker in familial hereditary cancer syndrome. KEY MESSAGES: RBBP8(p.E281*) is a susceptibility gene in this familial hereditary cancer syndrome RBBP8(p.E281*) lost its ability to enter the nucleus and the BRCA1 binding motif A novel RBBP8(p.E281*) germline mutation promotes breast cancer tumorigenesis Patients with RBBP8(p.E281*) germline mutation may benefit from Olaparib, Cisplatin.© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.