Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage

Raad, Sabine; Flaman, Jean–Michel; Bougeard, Gaëlle; Frébourg, Thierry; Tournier, Isabelle

doi:10.1093/hmg/ddx165

Cited by 14 publications

(2 citation statements)

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“…The p.R290H variant is often considered as a VUS in clinical practice primarily due to the lack of LFS phenotypic evidence (Arcand et al, 2008), its “supertrans” classification in yeast functional assays (Kato et al, 2003), in vitro studies showing apparently normal functional activity (Wang, Niu, Lam, Xiao, & Ren, 2014; Zerdoumi et al, 2017), and evidence of potential lack of segregation with disease (Quesnel et al, 1999). However, its presence is some LFS families reported in IARC, and its current LP classification by some clinical laboratories, warrant further evaluation to determine its true pathogenic potential.…”

Section: Discussionmentioning

confidence: 99%

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

et al. 2018

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Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 website. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555–5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400–865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype which is based upon cancer family history. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.

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Section: Discussionmentioning

confidence: 99%

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

et al. 2018

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“…Unlike loss-of-function variants (nonsense, frameshift, splicing, gross rearrangements), the interpretation of the most common TP53 missense variants is not always obvious. Furthermore, a subclass of missense variants exert a dominant-negative effect resulting in mutant proteins that form tetramers with wild-type TP53 , inhibiting the transcriptional activity of the protein complex and causing larger defects in response to DNA damage [ 6 – 10 ].…”

Section: Introductionmentioning

confidence: 99%

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Sánchez-Heras¹,

Cajal²,

Pineda³

et al. 2023

Clin Transl Oncol

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Li-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals.

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What 20 years of research has taught us about the TP53 p.R337H mutation

Pinto

Zambetti

2020

Cancer

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The p53 tumor suppressor transcriptionally regulates a myriad of genes involved in cell cycle control, DNA repair, cell survival, and cell metabolism and represents one of the most well-studied inhibitors of tumorigenesis. Since the discovery of TP53 in 1979, somatic mutations have been shown to be extremely common; more than 50% of human cancers carry loss-of-function mutations in TP53. Inherited or germline TP53 mutations are rare and are involved in complex hereditary cancer predisposition disorders, and affected family members can develop diverse tumor types and multiple primary cancers at young ages. In Brazil, a fascinating history of p53 and cancer predisposition began in the year 2000 with identification of the TP53 p.R337H mutation in close association with the development of adrenocortical tumors. In these past 20 years, much has been learned about the genetics and biochemistry of this mutation, which is widespread in Brazil because of a founder effect. This review highlights the contributions of TP53 p.R337H research over the last 20 years, the findings of which have sparked passionate debate among researchers worldwide, to understanding cancer predisposition in Brazilian individuals and families. Cancer 2020;126:4678-4686.

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Germline TP53 mutations result into a constitutive defect of p53 DNA binding and transcriptional response to DNA damage

Cited by 14 publications

References 0 publications

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

What 20 years of research has taught us about the TP53 p.R337H mutation

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