The function of a heterozygous p53 mutation in a Li-Fraumeni syndrome patient

• Published in: PloS one 2020-06, Vol.15 (6), p.e0234262-e0234262
• Main Authors: Li, Yang, Li, Ting, Tang, Yuejia, Zhan, Zhiyan, Ding, Lixia, Song, Lili, Yu, Tingting, Yang, Yi, Ma, Jing, Zhang, Yingwen, Zhou, Ying, Gu, Song, Xu, Min, Gao, Yijin, Li, Yanxin, Deb, Sumitra
• Format: Article
• Language: English
• Subjects: Apoptosis; Biology and Life Sciences; Cancer; Case studies; Cell division; Cell proliferation; Children & youth; Diagnosis; Fibroblasts; Gene mutation; Gene sequencing; Health risks; Hematology; Laboratories; Li, Yang; Li-Fraumeni syndrome; Medicine; Medicine and Health Sciences; Monoclonal antibodies; mRNA; Mutants; Mutation; Oct-4 protein; Oncology; p53 Protein; Pediatrics; Plasmids; Pluripotency; Proteins; Somatic cells; Stem cells; Tumor cells; Tumors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0234262

p53 is one of the most extensively studied proteins in cancer research. Mutations in p53 generally abolish normal p53 function, and some mutants can gain new oncogenic functions. However, the mechanisms underlying p53 mutation-driven cancer remains to be elucidated. Our study investigated the function of a heterozygous p53 mutation (p.Asn268Glufs*4) in a Li-Fraumeni syndrome (LFS) patient. We used episomal technology to perform somatic reprogramming, and used molecular and cell biology methods to determine the p53 mutation levels in patient-originated induced pluripotent stem (iPS) cells at the RNA and protein levels. We found that p53 protein expression was not increased in this patient's somatic cells compared with those of a healthy control. p53 mutation facilitates the proliferation of tumor cells by inhibiting apoptosis and promoting cell division. It can inhibit the efficiency of somatic reprogramming by inhibiting OCT4 expression during reprogramming stage. Moreover, not all p53 mutant iPS cell lines have mutant p53 RNA sequences. A small percentage of mutant p53 mRNA is present in the somatic cells from the patient and his mother. In summary, this p53 mutation can promote tumor cell proliferation, inhibit somatic reprogramming, and exhibit random p53 allelic expression of heterozygous mutations in the patient and iPS cells which may be one of the reasons why the people with p53 mutations develop cancer at random. This finding suggested that mutant p53 allelic expression should be added to the risk forecasting of cancer.