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A novel RBBP8(p.E281*) germline mutation is a predisposing mutation in familial hereditary cancer syndrome

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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

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Availability of data and material

The data that support the findings of our study are available from the corresponding author Shubing Zhang (shubingzhang@csu.edu.cn), upon reasonable request.

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Acknowledgements

We are thankful to the individual patients with hereditary cancer syndromes for contributing to our research.

Funding

This research work was supported by the National Natural Science Foundation of China (Grant Nos. 81972312, 81672632, and 82103184), the Natural Science Foundation of Hunan Province of China (Nos. 2021JJ30912 and 2021JJ40720), and the graduate student independent exploration and innovation project of Central South University (2021zzts0081 and 1053320215711).

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Author notes

  1. Jinhua Yan and Jinzheng Wu contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, The Second Xiangya Hospital, Central South University, Changsha, 410013, China

    Jinhua Yan & Jinzheng Wu

  2. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, 410013, China

    Jinhua Yan, Jinzheng Wu, Yang Wang, Xiaotang Di, Doudou Wen & Shubing Zhang

  3. Department of Biomedical Informatics, School of Life Sciences, Central South University, Changsha, 410013, China

    Hao Jiang

  4. Department of Pathology, the Second Xiangya Hospital, Central South University, Changsha, 410013, China

    Duo Li

  5. Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, 410013, China

    Shubing Zhang

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  1. Jinhua Yan
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Contributions

Jinhua Yan: methodology, formal analysis, data curation, investigation, writing (original draft), and visualization. Jinzheng Wu: planning, formal analysis, resources, data curation, writing (original draft), and visualization. Yang Wang: software, investigation, and writing (review and editing). Xiaotang Di: visualization, resources, and writing (review and editing). Hao Jiang: formal analysis, visualization, resources, and writing (review and editing). Doudou Wen: visualization, resources, and writing (review and editing). Duo Li: conceptualization, supervision, project administration, and writing (review and editing). Shubing Zhang: conceptualization, supervision, project administration, funding acquisition, resources, and writing (review and editing). The work reported in the paper has been performed by the authors unless clearly specified in the text.

Corresponding authors

Correspondence to Duo Li or Shubing Zhang.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the ethics committee of the School of Life Sciences, Central South University (No. 2022-1-13). All participants signed informed consent. The blood of the proband’s brother and sister was collected. CT, B-ultrasound imaging, and medical record investigation were performed on the subjects. The laboratory animals were approved by the medical laboratory animal ethics committee of the School of Life Sciences, Central South University (No. 2022-2-18).

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The authors declare no competing interests.

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Table 2 Patients with mutations genes (XLS 29 KB)

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Yan, J., Wu, J., Wang, Y. et al. A novel RBBP8(p.E281*) germline mutation is a predisposing mutation in familial hereditary cancer syndrome. J Mol Med 101, 1255–1265 (2023). https://doi.org/10.1007/s00109-023-02354-z

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