Revisiting Li-Fraumeni Syndrome From <i>TP53</i> Mutation Carriers

Bougeard, Gaëlle; Renaux-Petel, Mariette; Flaman, Jean–Michel; Charbonnier, Camille; Fermey, Pierre; Belotti, Muriel; Gauthier‐Villars, Marion; Stoppa‐Lyonnet, Dominique; Consolino, Émilie; Brugières, Laurence; Caron, Olivier; Benusiglio, Patrick R.; Paillerets, Brigitte Bressac-de; Bonadona, Valérie; Bonaïti‐Pellié, Catherine; Tinat, Julie; Baert‐Desurmont, Stéphanie; Frébourg, Thierry

doi:10.1200/jco.2014.59.5728

Cited by 569 publications

(634 citation statements)

References 39 publications

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“…Our results are consistent with those of Bougeard et al who, in a study published in 2015, conducted on 127 breast cancer patients and positive TP53 mutations reported that HER 2 alone was positive in 55% of cases and 37% of cases were triple positive [31].…”

Section: Tp53supporting

confidence: 93%

See 1 more Smart Citation

Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

Goidescu

Eniu

Caracostea

et al. 2018

Revista Romana De Medicina De Laborator

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Section: Tp53supporting

confidence: 93%

“…This observation is supported by other studies that have shown that breast cancer patients with positive TP53 mutation can associate HER2 -overexpressing forms in up to 82% of cases [30,31].…”

Section: Tp53supporting

confidence: 83%

Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

Goidescu

Eniu

Caracostea

et al. 2018

Revista Romana De Medicina De Laborator

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“…In a recent report on 322 TP53 mutation carriers from French Li -Fraumeni families, the mean age of tumor onset was statistically different between carriers of missense mutations (23.8 years) and those carrying nonsense mutations or genomic rearrangements (28.5 years). The difference was even larger when comparing hotspot mutations, such as p.R175H or p.R248W (mean age of tumor onset, 15 -20 yr) with complete deletion of the TP53 gene (38.5 yr) (Bougeard et al 2015). Assuming that complete deletion of TP53 represents a "straight" LOF effect, these observations suggest that the more severe clinical phenotype of hotspot mutants is caused by their capacity to impair the wild-type allele (DN effects) and/or by specific GOF effects.…”

Section: Classifying Tp53 Mutations For Clinical Usementioning

confidence: 97%

SomaticTP53Mutations in the Era of Genome Sequencing

Hainaut

Pfeifer

2016

Cold Spring Harb Perspect Med

181

141

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Amid the complexity of genetic alterations in human cancer, TP53 mutation appears as an almost invariant component, representing by far the most frequent genetic alteration overall. Compared with previous targeted sequencing studies, recent integrated genomics studies offer a less biased view of TP53 mutation patterns, revealing that .20% of mutations occur outside the DNA-binding domain. Among the 12 mutations representing each at least 1% of all mutations, five occur at residues directly involved in specific DNA binding, four affect the tertiary fold of the DNA-binding domain, and three are nonsense mutations, two of them in the carboxyl terminus. Significant mutations also occur in introns, affecting alternative splicing events or generating rearrangements (e.g., in intron 1 in sporadic osteosarcoma). In aggressive cancers, mutation is so common that it may not have prognostic value (all these cancers have impaired p53 function caused by mutation or by other mechanisms). In several other cancers, however, mutation makes a clear difference for prognostication, as, for example, in HER2-enriched breast cancers and in lung adenocarcinoma with EGFR mutations. Thus, the clinical significance of TP53 mutation is dependent on tumor subtype and context. Understanding the clinical impact of mutation will require integrating mutationspecific information (type, frequency, and predicted impact) with data on haplotypes and on loss of heterozygosity.

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“…Therefore, large-scale studies on the precise clinical significance of TP53 variants in introns and alternative exons are now required to improve our understanding of the significance of these regions (Box D). In the meantime, a pragmatic recommendation would be to consider the entire sequence of the TP53 gene for mutation screening strategies using NGS in sporadic cancers as well as in the germline of subjects who meet the criteria for TP53 mutation testing (80)(81)(82). …”

Section: Discussionmentioning

confidence: 99%

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

et al. 2017

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Accurate assessment of TP53 gene status in sporadic tumors and in the germline of individuals at high risk of cancer due to Li-Fraumeni Syndrome (LFS) has important clinical implications for diagnosis, surveillance, and therapy. Genomic data from more than 20,000 cancer genomes provide a wealth of information on cancer gene alterations and have confirmed TP53 as the most commonly mutated gene in human cancer. Analysis of a database of 70,000 TP53 variants reveals that the two newly discovered exons of the gene, exons 9b and 9g, generated by alternative splicing, are the targets of inactivating mutation events in breast, liver, and head and neck tumors. Furthermore, germline rearrangements in intron 1 of TP53 are associated with LFS and are frequently observed in sporadic osteosarcoma. In this context of constantly growing genomic data, we discuss how screening strategies must be improved when assessing TP53 status in clinical samples. Finally, we discuss how TP53 alterations should be described by using accurate nomenclature to avoid confusion in scientific and clinical reports.

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Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers

Abstract: The clinical gradient of the germline TP53 mutations, which should be validated by other studies, suggests that it might be appropriate to stratify the clinical management of LFS according to the class of the mutation.

Cited by 569 publications

References 39 publications

Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

Associations of pathogenic mutations responsible for breast cancer risk with histology and immunohistochemistry in Romanian population

SomaticTP53Mutations in the Era of Genome Sequencing

Recommended Guidelines for Validation, Quality Control, and Reporting of TP53 Variants in Clinical Practice

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