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A novel RBBP8(p.E281*) germline mutation is a predisposing mutation in familial hereditary cancer syndrome
Journal of Molecular Medicine ( IF 4.8 ) Pub Date : 2023-08-24 , DOI: 10.1007/s00109-023-02354-z
Jinhua Yan 1, 2 , Jinzheng Wu 1, 2 , Yang Wang 2 , Xiaotang Di 2 , Hao Jiang 3 , Doudou Wen 2 , Duo Li 4 , Shubing Zhang 2, 5
Affiliation  

Abstract

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



中文翻译:

一种新的 RBBP8(p.E281*) 种系突变是家族遗传性癌症综合征的易感突变

摘要

筛查肿瘤易感基因有助于识别用于遗传性癌症监测、预防和诊断的强大生物标志物,为了解遗传性癌症综合征的精确治疗的潜在分子机制和生物标志物提供机会。血液全外显子组测序和生物信息学分析发现,遗传性癌症综合征家族中存在一种新的 RBBP8(p.E281*) 种系突变,并经桑格测序验证。通过 CCK8、集落形成、Transwell 和体内异种移植试验研究细胞增殖、集落形成、细胞迁移和体内肿瘤发生。通过免疫荧光、核和细胞质蛋白提取试剂盒以及 Co-IP 检测蛋白质定位和相互作用。RBBP8(p.E281*) 基因的一个新的杂合种系突变被发现与家族遗传性癌症综合征相关。RBBP8-WT主要在细胞核中检测到并与BRCA1相互作用。相反,RBBP8(p.E281*)主要位于细胞质中,与BRCA1没有相互作用。RBBP8(p.E281*) 变体除了在细胞核中丧失功能外,还在细胞质中发挥致癌作用,促进乳腺癌增殖、体内肿瘤发生和迁移。与对照组相比,RBBP8(p.E281*) 对顺铂和奥拉帕尼治疗的反应显示细胞死亡增加。在家族遗传性癌症综合征中发现了一种新的 RBBP8(p.E281*) 种系突变。RBBP8(p.E281*) 无法进入细胞核或通过丢失的结合基序与 BRCA1 相互作用,并且 RBBP8(p.E281*) 变体除了在细胞核中丧失功能外,似乎还促进细胞质中的肿瘤发生。RBBP8(p.E281*) 变异体可能会促进肿瘤易感性,并可作为家族遗传性癌症综合征的精准医学生物标志物。

关键信息

  • RBBP8(p.E281*) 是这种家族遗传性癌症综合征的易感基因

  • RBBP8(p.E281*) 失去进入细胞核的能力和 BRCA1 结合基序

  • 一种新的 RBBP8(p.E281*) 种系突变促进乳腺癌肿瘤发生

  • 患有 RBBP8(p.E281*) 种系突变的患者可能会受益于奥拉帕尼、顺铂

更新日期:2023-08-25
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