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

Abstract

AbstractThe diagnosis of somatic and germlineTP53mutations 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 inTP53exons led to impairedTP53splicing as shown by an analysis of theTP53expression 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.