Changes

==Primary Author(s)*==

==Primary Author(s)*==

Beth Pitel, MS, ASCP(CG)CM

Beth Pitel, MS, ASCP(CG)CM

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==Gene Overview==

==Gene Overview==

TP53, encoding p53, is an oncogene, tumor suppressor, and regulator of DNA repair. Inactivating TP53 mutations are common in human tumors and they are a hallmark of a hereditary cancer predisposition disorder known as Li-Fraumeni syndrome [1-4].

''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 (figure 1) [5]. One of its best-understood functions are to promote cell cycle arrest and apoptosis, as a “guardian of the genome” [5]. 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 [8]. 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) [5].  

''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 [5]. One of its best-understood functions is to promote cell cycle arrest and apoptosis, as a “guardian of the genome” [5]. 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 [8]. 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) [5].  

''Mutational spectrum'' - Approximately half of all cancers harbor a TP53 mutation, though the frequency and the distribution of mutations can vary between tumor types (figure 2) [5]. 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) [5]. Approximately 25% of TP53 mutations are nonsense or frameshift mutations; the remainders are splice site SNVs and in-frame indels of unclear biological significance [5]. Biallelic loss of TP53 commonly occurs via segmental deletion; the deletions vary widely in size and occur at a frequency similar to p53 SNVs. About 25% of tumors harbor the canonical p53 missense mutation/deletion combination, but all other potential variant combinations leading to biallelic loss of function are seen [5,9].

''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 [5]. 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) [5]. Approximately 25% of ''TP53'' mutations are nonsense or frameshift mutations; the remainders are splice site SNVs and in-frame indels of unclear biological significance [5]. 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].

In some cancers, TP53 mutations co-occur with activating KRAS mutations or MYC amplification, demonstrating the cooperation of p53 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 [12]. 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 may contribute to carcinogenesis [12].

''p53 in cancer'' - ''TP53'' mutations may occur early in the natural history of esophageal and hepatic carcinomas [12]. ''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 [12].

''Li-Fraumeni Syndrome'' - Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder that is commonly associated with germline mutations of TP53 [13]. The 2009 ‘revised’ Chompret criteria for LFS are [14]:

''Li-Fraumeni Syndrome'' - Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder that is commonly associated with germline mutations of ''TP53'' [13]. The 2009 ‘revised’ Chompret criteria for LFS are [14]:

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

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

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

 

3. Patient with adrenocortical carcinoma or choroid plexus tumor, irrespective of family history.

==Common Alteration Types==

==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 [15]. 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 [15]); 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 [15].

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 [15]. 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 [15]); 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 [15].

{| class="wikitable sortable"

{| class="wikitable sortable"

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! Copy Number Loss   !! Copy Number Gain   !! LOH   !!   Loss-of-Function Mutation   !! Gain-of-Function Mutation !! Translocation/Fusion  

!Copy Number Loss!!Copy Number Gain!!LOH!!Loss-of-Function Mutation!!Gain-of-Function Mutation!!Translocation/Fusion

|-

|-

| X || || X || X || X ||

|X|| ||X||X||X||

|}

|}

15. Baugh EH, et al., (2018). Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25(1):154-160, PMID 29099487.  

15. Baugh EH, et al., (2018). Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25(1):154-160, PMID 29099487.  

== Notes ==

 

 

==Notes==

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

[[Category:Cancer Genes T]]

[[Category:Cancer Genes T]]

[[Category:Tumor Suppressor Genes T]]

[[Category:Tumor Suppressor Genes T]]

[[Category:Oncogenes T]]

[[Category:Oncogenes T]]