Kay Weng Choy, MBBS, Monash Medical Centre
Beth Pitel, MS, ASCP(CG)CM
Tumor protein p53, LFS1, p53, BCC7, TRP53
Nearly universal involvement in diverse cancer types.
TP53, encoding p53, is an oncogene, tumor suppressor, and regulator of DNA repair. TP53 has been implicated in many cancer types, is classically considered the prototypic tumor suppressor gene, and inactivating TP53 mutations are also a hallmark of a hereditary cancer predisposition disorder known as Li-Fraumeni syndrome [1-4,16-17].
Function - p53 is a DNA-binding protein that regulates transcription. A variety of regulators control the activity of p53 which in turn governs many biological processes. See Figure 1 in . One of its best-understood functions is to promote cell cycle arrest and apoptosis, as a “guardian of the genome” . It is crucial for a reversible DNA damage-induced G1 phase checkpoint that is mediated by its ability to transcriptionally activate the p21 cyclin-dependent kinase inhibitor gene, likely facilitating DNA repair prior to further cell division [5-7]. p53 induces cellular senescence, a stable cell cycle arrest program that involves the retinoblastoma gene product . p53 promotes apoptosis by inducing pro-apoptotic BCL-2 family members which enable caspase activation and cell death. As p53 is activated to promote the elimination or repair of damaged cells, this reduces the risk of propagating mutations. In addition, p53 stimulates DNA repair by activating genes that encode components of the DNA-repair machinery. DNA damage response kinases phosphorylate p53, leading to cell-cycle arrest, senescence, or apoptosis. Recent work suggests that p53 also controls ‘non-canonical’ programs; p53 can influence autophagy, modify metabolism, suppress pluripotency and cellular plasticity, and facilitate ferroptosis (an iron-dependent form of cell death) .
Mutational spectrum - Approximately half of all cancers harbor a TP53 mutation, though the frequency and the distribution of mutations can vary between tumor types. See Figure 2 in . The most common TP53 mutations are missense mutations in the DNA-binding domain. Most of the TP53 single-nucleotide variants (SNVs) are missense mutations (25% of these mutations are five ‘hotspot’ mutations) . Approximately 25% of TP53 mutations are nonsense or frameshift mutations; the remainders are splice site SNVs and in-frame indels of unclear biological significance . Biallelic loss of TP53 commonly occurs via segmental deletion; the deletions vary widely in size and occur at a frequency similar to TP53 SNVs. About 25% of tumors harbor the canonical TP53 missense mutation/deletion combination, but all other potential variant combinations leading to biallelic loss of function are seen [5,9]. In some cancers, TP53 mutations co-occur with activating KRAS mutations or MYC amplification, demonstrating the cooperation of TP53 with oncogenes to transform primary cells. Genomic copy number variation (a marker of genetic instability) is higher in patients with germline TP53 mutations than in healthy subjects [5,10,11].
p53 in cancer - TP53 mutations may occur early in the natural history of esophageal and hepatic carcinomas . TP53 mutations may abrogate stress-induced tissue remodeling constraints, hence providing a short-term proliferative advantage due to altered regulation of apoptosis/senescence pathways, which could contribute to carcinogenesis .
p53 testing for diagnosis and prognosis in breast cancer - Breast cancer studies have consistently demonstrated the association of TP53 mutations with poor prognosis; TP53 mutation status is strongly associated with the two breast cancer immunohistological subtypes that carry the poorest prognosis, basal-like and ERBB2+ . Truncating TP53 mutations have been associated with poorer outcomes in several breast cancer cohorts, compared to single nucleotide variants .
Li-Fraumeni Syndrome - Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder that is commonly associated with germline mutations of TP53 . The 2009 ‘revised’ Chompret criteria for LFS are :
1. Proband with tumor belonging to LFS tumor spectrum (e.g., soft tissue sarcoma, osteosarcoma, brain tumor, premenopausal breast cancer, adrenocortical carcinoma, leukemia, lung bronchoalveolar cancer) before age 46 years AND at least one first- or second-degree relative with LFS tumor (except breast cancer if proband has breast cancer) before age 56 years or with multiple tumors; OR
2. Proband with multiple tumor (except multiple breast tumors), two of which belong to LFS tumor spectrum and first of which occurred before age 46 years; OR
3. Patient with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history.
Common Alteration Types
The TP53 gene contains homozygous mutations in about 50-60% of human cancers. About 90% of the mutations in TP53 encode missense mutant proteins that span about 190 codons in the DNA-binding domain; none of the 50 most common pathogenic missense mutations occur outside of the DNA-binding region. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates p53 transcriptional pathway . The eight most common mutations across all cancer types (R175H, R248Q, R273H, R248W, R273C, R282W, G245S, R249S) are found in codons that account for about 28% of the total p53 mutations (See Table 1 in ); these alleles appear to be selected for preferentially in human cancers of many tissue types. Seven of the eight mutations occur at methylated CpG sites in TP53, which encode arginine residues that contact the DNA and are conserved over evolutionary time scales .
Inactivating mutations resulting in loss of p53 function, including deletions, LOH, and loss of function (LOF) alterations often confer a poor prognosis and chemoresistance. Alternatively, gain-of-function mutations promoting the expression and stability of the p53 protein in the nucleus can also lead to oncogenic effects, including genomic instability and excessive cell proliferation .
|Copy Number Loss||Copy Number Gain||LOH||Loss-of-Function Mutation||Gain-of-Function Mutation||Translocation/Fusion|
TP53 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
TP53 by COSMIC - sequence information, expression, catalogue of mutations
TP53 by CIViC - general knowledge and evidence-based variant specific information
TP53 by IARC - TP53 database with reference sequences and mutational landscape
TP53 by St. Jude ProteinPaint mutational landscape and matched expression data.
TP53 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
TP53 by Cancer Index - gene, pathway, publication information matched to cancer type
TP53 by OncoKB - mutational landscape, mutation effect, variant classification
TP53 by My Cancer Genome - brief gene overview
TP53 by UniProt - protein and molecular structure and function
TP53 by Pfam - gene and protein structure and function information
TP53 by GeneCards - general gene information and summaries
GeneReviews - information on Li Fraumeni Syndrome
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