@article{96b4c5e7bb70456fba903395520fb4da,
title = "Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas",
abstract = "The TP53 tumor suppressor gene is frequently mutated in human cancers. An analysis of five data platforms in 10,225 patient samples from 32 cancers reported by The Cancer Genome Atlas (TCGA) enables comprehensive assessment of p53 pathway involvement in these cancers. More than 91% of TP53-mutant cancers exhibit second allele loss by mutation, chromosomal deletion, or copy-neutral loss of heterozygosity. TP53 mutations are associated with enhanced chromosomal instability, including increased amplification of oncogenes and deep deletion of tumor suppressor genes. Tumors with TP53 mutations differ from their non-mutated counterparts in RNA, miRNA, and protein expression patterns, with mutant TP53 tumors displaying enhanced expression of cell cycle progression genes and proteins. A mutant TP53 RNA expression signature shows significant correlation with reduced survival in 11 cancer types. Thus, TP53 mutation has profound effects on tumor cell genomic structure, expression, and clinical outlook. Donehower et al. performed a comprehensive analysis of the effects of TP53 gene mutation in 32 cancer types and 10,225 patients from The Cancer Genome Atlas (TCGA). Data synthesized from five different analysis platforms show how mutant TP53 increases genomic instability and induces major pathway signaling changes in cancer cells.",
keywords = "PanCanAtlas, TCGA, TP53, TP53 mutation, The Cancer Genome Atlas, chromosomal instability, p53, p53 signaling pathway, p53 signature, p53 targets",
author = "{The Cancer Genome Atlas Network} and Donehower, {Lawrence A.} and Thierry Soussi and Anil Korkut and Yuexin Liu and A. Schultz and M. Cardenas and X. Li and O. Babur and Hsu, {Teng Kuei} and Olivier Lichtarge and Weinstein, {John N.} and R. Akbani and Wheeler, {David A.}",
note = "Funding Information: We thank Tajhal Dayaram for editorial assistance on the manuscript. We are also grateful for funding from multiple sources: NIH/NCI U24 CA210950, U24 CA210949, U24 CA199461, UM1HG008898, and P30 CA016672; and DoD/CDMRP W81XWH-16-1-0237. Personal grants for T.S. to support the development of the UMD_TP53 database were received from Radiumhemmets Forskningsfonder. The Cancer Genome Atlas Research (TCGA) Network contributed collectively to the acquisition of patient samples and the generation of data underlying this study. Data generation and analyses were performed by Genome Sequencing Centers, Genome Characterization Centers, and Genome Data Analysis Centers. The efforts reported here were also assisted by TCGA Pan-Cancer Analysis Project. The authors in this p53 pathway-specific analysis group included L.A.D. who analyzed much of the data presented and wrote the manuscript; D.A.W. who led and organized the study, assisted in the analysis of TP53 sequencing data, and helped edit the manuscript; T.S. who performed analysis of the TP53 mutations, contributed to the generation of Figures 1, 2, and S1–S3, and helped in the editing of the paper; A.K. who provided data analyses for Figures 4 and 6, and edited the statistical analyses throughout the paper; Y.L. who contributed the reverse-phase protein array (RPPA) analysis that is the basis for Figures 5 and S7; R.A. who performed analyses on p53 pathway activity and PanCanAtlas expression data and provided computational expertise for some of the analyses; A.S. who performed TP53 pathway and mRNA expression computational analyses; J.N.W. who led the computational scientists assisting this effort and provided editing assistance on the paper; M.C. who extracted and analyzed individual TP53 sequencing reads from the Genomic Data Commons (GDC) portal and who assisted in the analyses shown in Figure 2; X.L. and O.B. who performed the mutual exclusivity analyses in Figure 6; and T.-K.H. and O.L. who assisted on the role of TP53 mutations in patient survival shown in Figure 7. The authors declare no competing interests. Funding Information: We thank Tajhal Dayaram for editorial assistance on the manuscript. We are also grateful for funding from multiple sources: NIH/NCI U24 CA210950 , U24 CA210949 , U24 CA199461 , UM1HG008898 , and P30 CA016672 ; and DoD/CDMRP W81XWH-16-1-0237 . Personal grants for T.S. to support the development of the UMD_TP53 database were received from Radiumhemmets Forskningsfonder . Publisher Copyright: {\textcopyright} 2019 The Author(s)",
year = "2019",
month = jul,
day = "30",
doi = "10.1016/j.celrep.2019.07.001",
language = "English (US)",
volume = "28",
pages = "1370--1384.e5",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}