| Author | Abreu, Renata B. V. | |
| Author | Pereira, Ariane S. | |
| Author | Rosa, Marcela N. | |
| Author | Ashton‑Prolla, Patricia | |
| Author | Silva, Viviane A. O. | |
| Author | Melendez, Matias E. | |
| Author | Palmero, Edenir I. | |
| Access date | 2024-12-14T11:31:20Z | |
| Available date | 2024-12-14T11:31:20Z | |
| Document date | 2024 | |
| Citation | ABREU, Renata B. V. et al. Functional evaluation of germline TP53 variants identified in Brazilian families at-risk for Li–Fraumeni syndrome. Scientific Reports, v. 14, n. 17187, p. 1-10, 2024. | en_US |
| ISSN | 2045-2322 | en_US |
| URI | https://www.arca.fiocruz.br/handle/icict/67594 | |
| Description | Supplementary Information Te online version contains supplementary material available at https://doi.org/10.1038/s41598-024-67810-3. | en_US |
| Sponsorship | Tis work was supported by São Paulo Research Foundation (FAPESP, grant number 2018/25118-8) and National Oncology Care Support Program (PRONON, Grant Number 25000.056766/2015-64), from the Brazilian Ministry of Health. | en_US |
| Language | eng | en_US |
| Publisher | Nature | en_US |
| Rights | open access | en_US |
| Subject in Portuguese | Análise funcional | en_US |
| Subject in Portuguese | Fator de transcrição | en_US |
| Subject in Portuguese | Reparo de DNA | en_US |
| Subject in Portuguese | Síndrome Li–Fraumeni | en_US |
| Title | Functional evaluation of germline TP53 variants identifed in Brazilian families at‑risk for Li–Fraumeni syndrome | en_US |
| Type | Article | en_US |
| DOI | 10.1038/s41598-024-67810-3 | |
| Abstract | Germline TP53 pathogenic variants can lead to a cancer susceptibility syndrome known as Li–Fraumeni (LFS). Variants afecting its activity can drive tumorigenesis altering p53 pathways and their identifcation is crucial for assessing individual risk. This study explored the functional impact of TP53 missense variants on its transcription factor activity. We selected seven TP53 missense variants (c.129G>C, c.320A>G, c.417G>T, c.460G>A, c,522G>T, c.589G>A and c.997C>T) identifed in Brazilian families at-risk for LFS. Variants were created through site-directed mutagenesis and transfected into SK-OV-3 cells to assess their transcription activation capabilities. Variants K139N and V197M displayed signifcantly reduced transactivation activity in a TP53-dependent luciferase reporter assay. Additionally, K139N negatively impacted CDKN1A and MDM2 expression and had a limited efect on GADD45A and PMAIP1 upon irradiation-induced DNA damage. Variant V197M demonstrated functional impact in all target genes evaluated and loss of Ser15 phosphorylation. K139N and V197M variants presented a reduction of p21 levels after irradiation. Our data show that K139N and V197M negatively impact p53 functions, supporting their classifcation as pathogenic variants. This underscores the signifcance of conducting functional studies on germline TP53 missense variants classifed as variants of uncertain signifcance to ensure proper management of LFS-related cancer risks. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil / Fundação Oswaldo Cruz. Instituto Carlos Chagas. Laboratório de Biologia Básica de Células-tronco. Curitiba, PR, Brasil. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil. | en_US |
| Affilliation | Hospital de Clínicas de Porto Alegre. Experimental Research Center. Porto Alegre, RS, Brasil / Universidade Federal do Rio Grande do Sul. Department of Genetics. Porto Alegre, RS, Brasil. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil / Federal University of Bahia. School of Medicine. Department of Pathology. Salvador, BA, Brasil / Fundação Oswaldo Cruz. Instituto Gonçalo Moniz. Salvador, BA, Brasil. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil / Brazilian National Cancer Institute. Molecular Carcinogenesis Program. Rio de Janeiro, RJ, Brasil. | en_US |
| Affilliation | Barretos Cancer Hospital. Molecular Oncology Research Center. Barretos, SP, Brasil / Brazilian National Cancer Institute. Department of Genetics. Rio de Janeiro, RJ, Brasil. | en_US |
| Subject | TP53 | en_US |
| Subject | Variants of uncertain signifcance | en_US |
| Subject | Functional analysis | en_US |
| Subject | Transcription factor | en_US |
| Subject | DNA repair | en_US |
| Subject | Li–Fraumeni syndrome | en_US |
| DeCS | Síndrome de Li-Fraumeni | en_US |
| DeCS | Genes p53 | en_US |
