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==Primary Author(s)*==

==Primary Author(s)*==

Beth Pitel, MS, ASCP(CG)CM

Beth Pitel, MS, ASCP(CG)CM

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''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)

''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.

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].

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 [12].

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 [12].

{| 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

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

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

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17. Kato S, et al., (2003). Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 100(14):8424-8429, PMID 12826609.

17. Kato S, et al., (2003). Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Proc Natl Acad Sci USA 100(14):8424-8429, PMID 12826609.

== 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]]