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Age-dependent copy number variations of TP53 tumour suppressor gene associated with altered phosphorylation status of p53 protein in sporadic schwannomas

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Abstract

Purpose

Point mutations of TP53 tumour suppressor are very rare in schwannomas. We aim to characterize the frequency of exonic copy-number changes of the gene in the tumour and to examine the association between TP53 alterations, phosphorylation status of p53 protein and clinical phenotypes.

Methods

The alterations of TP53 were screened by a combination of Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) in a total of 44 vestibular schwannomas. The mutation index (MI) in a tumour was defined as the number of exons mutated/ the number of exons tested. Phosphorylation status of p53 protein was investigated by immunoblotting and immunofluorescence.

Results

MLPA analysis showed single and multi-exon deletion mutations of TP53 in 65.7% of the cases. Comparisons of clinical features between mutated and non-mutated patients established an association of TP53 mutations with progressive phenotypes, including an earlier formation and a larger tumour. In addition, there were significant correlations between MI and both patients’ age and tumour size. The Ser 392 phosphorylation level of p53 varied among tumours, and correlation analysis revealed an age-dependent phosphorylation pattern. The majority of tumours with hyperphosphorylated p53 were from mutated and young patients, suggesting an association of Ser392 phosphorylation with the mutational status of TP53 involved in the acceleration of tumour growth in young individuals. Moreover, Ser 392 phosphorylation contributed to a nuclear accumulation of p53 in schwannona cultures with TP53 mutation.

Conclusions

An interplay between the mutation status of TP53, phosphorylation patterns and tumour behaviors might be established in the disease.

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Acknowledgements

This research was funded by the National Natural Science Foundation of China (Grant No. 81800898 to Hongsai Chen, No. 81670919 and No. 81870713 to Zhaoyan Wang, No. 81570906 to Hao Wu, No. 81700900 to Weidong Zhu and No. 81600815 to Yongchuan Chai).

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Author notes

  1. Hongsai Chen, He Huang, Jingjing Zhao and Zhigang Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Otolaryngology Head & Neck Surgery, The Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, No. 639, Zhi-Zao-Ju Road, Shanghai, 200011, China

    Hongsai Chen, He Huang, Jingjing Zhao, Zhigang Wang, Lu Xue, Weidong Zhu, Yongchuan Chai, Gen Li, Zhaoyan Wang & Hao Wu

  2. Ear Institute, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Hongsai Chen, He Huang, Jingjing Zhao, Zhigang Wang, Lu Xue, Weidong Zhu, Yongchuan Chai, Gen Li, Zhaoyan Wang & Hao Wu

  3. Shanghai Key Laboratory of Translational Medicine On Ear and Nose Diseases, Shanghai, China

    Hongsai Chen, He Huang, Jingjing Zhao, Zhigang Wang, Lu Xue, Weidong Zhu, Yongchuan Chai, Gen Li, Zhaoyan Wang & Hao Wu

  4. Shanghai Institute of Precision Medicine, The Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Hongsai Chen

  5. Department of Burn and Plastic Surgery, Shanghai Jiao Tong University, School of Medicine, Rui Jin Hospital, Shanghai, China

    Mengling Chang

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  1. Hongsai Chen
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Chen, H., Huang, H., Zhao, J. et al. Age-dependent copy number variations of TP53 tumour suppressor gene associated with altered phosphorylation status of p53 protein in sporadic schwannomas. J Neurooncol 143, 369–379 (2019). https://doi.org/10.1007/s11060-019-03176-1

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