Blood functional assay for rapid clinical interpretation of germline <i>TP53</i> variants

Raad, Sabine; Rolain, Marion; Coutant, Sophie; Derambure, Céline; Charbonnier, Françoise; Bou, Jacqueline; Bouvignies, Emilie; Lienard, Gwendoline; Vasseur, Stéphanie; Farrell, Michael; Ingster, Olivier; Desurmont, Sophie; Kasper, Edwige; Bougeard, Gaëlle; Frébourg, Thierry; Tournier, Isabelle

doi:10.1136/jmedgenet-2020-107059

Cited by 9 publications

(6 citation statements)

References 34 publications

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“…As such, individuals with these variants remain underinformed about their potential for cancer risk and ineligible for advanced cancer screening by MRI that is offered to Li Fraumeni carriers. Recently, some groups have attempted to address this issue, by establishing the functionality of p53 variants in nontransformed cell lines containing endogenous p53 variants following exposure to genotoxic stress ( 36 , 37 ). However, such studies have been low throughput, and they require a genotoxic stress.…”

Section: Discussionmentioning

confidence: 99%

Common activities and predictive gene signature identified for genetic hypomorphs of TP53

Leung

Leu

Indeglia

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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Missense mutations that inactivate p53 occur commonly in cancer, and germline mutations in TP53 cause Li Fraumeni syndrome, which is associated with early-onset cancer. In addition, there are over two hundred germline missense variants of p53 that remain uncharacterized. In some cases, these germline variants have been shown to encode lesser-functioning, or hypomorphic, p53 protein, and these alleles are associated with increased cancer risk in humans and mouse models. However, most hypomorphic p53 variants remain un- or mis-classified in clinical genetics databases. There thus exists a significant need to better understand the behavior of p53 hypomorphs and to develop a functional assay that can distinguish hypomorphs from wild-type p53 or benign variants. We report the surprising finding that two different African-centric genetic hypomorphs of p53 that occur in distinct functional domains of the protein share common activities. Specifically, the Pro47Ser variant, located in the transactivation domain, and the Tyr107His variant, located in the DNA binding domain, both share increased propensity to misfold into a conformation specific for mutant, misfolded p53. Additionally, cells and tissues containing these hypomorphic variants show increased NF-κB activity. We identify a common gene expression signature from unstressed lymphocyte cell lines that is shared between multiple germline hypomorphic variants of TP53 , and which successfully distinguishes wild-type p53 and a benign variant from lesser-functioning hypomorphic p53 variants. Our findings will allow us to better understand the contribution of p53 hypomorphs to disease risk and should help better inform cancer risk in the carriers of p53 variants.

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Section: Discussionmentioning

confidence: 99%

Common activities and predictive gene signature identified for genetic hypomorphs of TP53

Leung

Leu

Indeglia

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…However, despite large-scale characterization of pediatric cancer genomes, there are typically variants identified in cancer-related genes for which no known functional impact on cancer onset or progression can be discerned. This reality applies even to the most frequently mutated genes in cancer such as TP53, although exciting new approaches to contextualizing variants in this gene have been recently published [ 14 , 15 ].…”

Section: Overview Of Genomic Toolsmentioning

confidence: 99%

Overview of modern genomic tools for diagnosis and precision therapy of childhood solid cancers

Mardis

2023

Current Opinion in Pediatrics

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Purpose of review The application of technology and computational analyses to generate new data types from pediatric solid cancers is transforming diagnostic accuracy. This review provides an overview of such new capabilities in the pursuit of improved treatment for essentially rare and underserved diseases that are the highest cause of mortality in children over one year of age. Sophisticated ways of identifying therapeutic vulnerabilities for highly personalized treatment are presented alongside cutting-edge disease response monitoring by liquid biopsy. Recent findings Precision molecular profiling data are now being combined with conventional pathology-based evaluation of pediatric cancer tissues. The resulting diagnostic information can be used to guide therapeutic decision-making, including the use of small molecule inhibitors and of immunotherapies. Integrating somatic and germline variant profiles constitutes a critical component of this emerging paradigm, as is tissue-of-origin derivation from methylation profiling, and rapid screening of potential therapies. These new approaches are poised for use in disease response and therapy resistance monitoring. Summary The integration of clinical molecular profiling data with pathology can provide a highly precise diagnosis, identify therapeutic vulnerabilities, and monitor patient responses, providing next steps toward precision oncology for improved outcomes, including reducing lifelong treatment-related sequelae.

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“…In terms of clinical approaches, diagnostic tests are under development that show the potential to provide personalized cancer risk assessments. Recent investigations demonstrated that TP53 variant carriers can be discriminated from wild-type p53 carriers by measuring functional and molecular characteristics such as p53 target gene expression patterns or DNA-binding capacity ( 71-73 ). Raad and coworkers ( 71 ) developed a blood-based assay where peripheral blood mononuclear cells are cultured, activated, treated with doxorubicin, and probed for the expression of p53 and its target genes.…”

Section: Improving Tp53 Variant Classificationsmentioning

confidence: 99%

“…Recent investigations demonstrated that TP53 variant carriers can be discriminated from wild-type p53 carriers by measuring functional and molecular characteristics such as p53 target gene expression patterns or DNA-binding capacity ( 71-73 ). Raad and coworkers ( 71 ) developed a blood-based assay where peripheral blood mononuclear cells are cultured, activated, treated with doxorubicin, and probed for the expression of p53 and its target genes. They discovered distinct functional profiles when comparing 8 P/LP variant carriers with 51 wild-type individuals, and, importantly, this strategy could be applied to VUS and low penetrance alleles.…”

Section: Improving Tp53 Variant Classificationsmentioning

confidence: 99%

Emerging insights into ethnic-specific TP53 germline variants

Fischer

Vivian

Gariépy

2023

JNCI: Journal of the National Cancer Institute

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The recent expansion of human genomics repositories has facilitated the discovery of novel TP53 variants in populations of different ethnic origins. Interpreting TP53 variants is a major clinical challenge as they are functionally diverse, confer highly variable predisposition to cancer (including elusive low-penetrance alleles), and interact with genetic modifiers that alter tumor susceptibility. Here, we discuss how a cancer risk continuum may relate to germline TP53 mutations based on our current review of genotype-phenotype studies and an integrative analysis combining functional and sequencing datasets. Our study reveals that each ancestry contains a distinct TP53 variant landscape defined by enriched ethnic-specific alleles. In particular, the discovery and characterization of suspected low-penetrance ethnic-specific variants with unique functional consequences, including P47S (African), G334R (Ashkenazi Jewish), and rs78378222 (Icelandic), may provide new insights in terms of managing cancer risk and the efficacy of therapy. Additionally, our analysis highlights infrequent variants linked to milder cancer phenotypes in various published reports that may be underdiagnosed and require further investigation, including D49H in East Asians and R181H in Europeans. Overall, the sequencing and projected functions of TP53 variants arising within ethnic populations, their interplay with modifiers, as well as the emergence of CRISPR screens and AI tools are now rapidly improving our understanding of the cancer susceptibility spectrum, leading towards more accurate and personalized cancer risk assessments.

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Blood functional assay for rapid clinical interpretation of germline TP53 variants

Cited by 9 publications

References 34 publications

Common activities and predictive gene signature identified for genetic hypomorphs of TP53

Common activities and predictive gene signature identified for genetic hypomorphs of TP53

Overview of modern genomic tools for diagnosis and precision therapy of childhood solid cancers

Emerging insights into ethnic-specific TP53 germline variants

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