TP53 mutations, expression and interaction networks in human cancers

Abstract

Although the associations of p53 dysfunction, p53 interaction networks and oncogenesis have been widely explored, a systematic analysis of TP53 mutations and its related interaction networks in various types of human cancers is lacking. Our study explored the associations of TP53 mutations, gene expression, clinical outcomes, and TP53 interaction networks across 33 cancer types using data from The Cancer Genome Atlas (TCGA). We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation. We identified genes potentially repressed by p53, and genes whose expression correlates significantly with TP53 expression. These gene products may be especially important nodes in p53 interaction networks in human cancers. This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers. Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes. We identified a set of candidate synthetic lethal (SL) genes for TP53, and validated some of these SL interactions using data from the Cancer Cell Line Project. These predicted SL genes are promising candidates for experimental validation and the development of personalized therapeutics for patients with TP53-mutated cancers.

TP53mutations promote immunogenic activity in breast cancer

“…P53 plays important roles in regulating the cancer-associated pathways such as cell cycle, apoptosis, DNA damage repair, autophagy, metabolism, inflammation, epithelial–mesenchymal transition (EMT), angiogenesis, and metastasis [50]. Accordingly, TP53 mutations often result in disturbances of the pathways regulated by p53 [58]. Indeed, we found that a number of p53-regulated pathways showed significantly differential activities between TP53 -mutated and TP53 -wildtype BCs such as the p53, cell cycle, apoptosis, Jak-STAT, NOD-like receptor, glycolysis, and Wnt pathways showing significantly higher activities in TP53 -mutated BCs than in TP53 -wildtype BCs (Mann-Whitney U test, P<0.05).…”

Genomic landscape and mutational impacts of recurrently mutated genes in cancers

“…Large‐scale cancer genomics projects like International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) provide opportunities for the integrative analysis in pan‐cancer at multiple omics levels (Gong et al., ). TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, ). Kandoth et al.…”

“…Large-scale cancer genomics projects like International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) provide opportunities for the integrative analysis in pan-cancer at multiple omics levels (Gong et al, 2017). TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, 2017). Kandoth et al investigated 127 significantly mutated genes in 12 cancers and categorized them into 20 cellular processes, including Wnt/β-catenin, MAPK, and PI3K signaling pathways (Kandoth et al, 2013).…”

Exploration of immunogene in colon cancer recurrence

“…We identified a set of candidate synthetic lethal (SL) genes [38] for 31 immune genes from above results. 19 SL genes for 6 immune genes have been found in mutation data (Table 3).…”