Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries

Abstract The diagnosis of somatic and germline TP53 mutations in human tumors or in individuals prone to various types of cancer has now reached the clinic. To increase the accuracy of the prediction of TP53 variant pathogenicity, we gathered functional data from three independent large-scale satura...

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Autores principales:	Vincent Carbonnier, Bernard Leroy, Shai Rosenberg, Thierry Soussi
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/0b0146cc59364ff9b0de255c6286014d
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spelling	oai:doaj.org-article:0b0146cc59364ff9b0de255c6286014d2021-12-02T16:08:54ZComprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries10.1038/s41598-020-74892-22045-2322https://doaj.org/article/0b0146cc59364ff9b0de255c6286014d2020-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-74892-2https://doaj.org/toc/2045-2322Abstract The diagnosis of somatic and germline TP53 mutations in human tumors or in individuals prone to various types of cancer has now reached the clinic. To increase the accuracy of the prediction of TP53 variant pathogenicity, we gathered functional data from three independent large-scale saturation mutagenesis screening studies with experimental data for more than 10,000 TP53 variants performed in different settings (yeast or mammalian) and with different readouts (transcription, growth arrest or apoptosis). Correlation analysis and multidimensional scaling showed excellent agreement between all these variables. Furthermore, we found that some missense mutations localized in TP53 exons led to impaired TP53 splicing as shown by an analysis of the TP53 expression data from the cancer genome atlas. With the increasing availability of genomic, transcriptomic and proteomic data, it is essential to employ both protein and RNA prediction to accurately define variant pathogenicity.Vincent CarbonnierBernard LeroyShai RosenbergThierry SoussiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Vincent Carbonnier Bernard Leroy Shai Rosenberg Thierry Soussi Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
description	Abstract The diagnosis of somatic and germline TP53 mutations in human tumors or in individuals prone to various types of cancer has now reached the clinic. To increase the accuracy of the prediction of TP53 variant pathogenicity, we gathered functional data from three independent large-scale saturation mutagenesis screening studies with experimental data for more than 10,000 TP53 variants performed in different settings (yeast or mammalian) and with different readouts (transcription, growth arrest or apoptosis). Correlation analysis and multidimensional scaling showed excellent agreement between all these variables. Furthermore, we found that some missense mutations localized in TP53 exons led to impaired TP53 splicing as shown by an analysis of the TP53 expression data from the cancer genome atlas. With the increasing availability of genomic, transcriptomic and proteomic data, it is essential to employ both protein and RNA prediction to accurately define variant pathogenicity.
format	article
author	Vincent Carbonnier Bernard Leroy Shai Rosenberg Thierry Soussi
author_facet	Vincent Carbonnier Bernard Leroy Shai Rosenberg Thierry Soussi
author_sort	Vincent Carbonnier
title	Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
title_short	Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
title_full	Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
title_fullStr	Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
title_full_unstemmed	Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries
title_sort	comprehensive assessment of tp53 loss of function using multiple combinatorial mutagenesis libraries
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/0b0146cc59364ff9b0de255c6286014d
work_keys_str_mv	AT vincentcarbonnier comprehensiveassessmentoftp53lossoffunctionusingmultiplecombinatorialmutagenesislibraries AT bernardleroy comprehensiveassessmentoftp53lossoffunctionusingmultiplecombinatorialmutagenesislibraries AT shairosenberg comprehensiveassessmentoftp53lossoffunctionusingmultiplecombinatorialmutagenesislibraries AT thierrysoussi comprehensiveassessmentoftp53lossoffunctionusingmultiplecombinatorialmutagenesislibraries
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Comprehensive assessment of TP53 loss of function using multiple combinatorial mutagenesis libraries

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