Abstract
Inactivation of wild-type p53 tumor suppressor function is the primary mechanism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with germline p53 mutations. Tumors derived from LFS patients frequently retain the normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA tumor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS families, each of whom presented with multiple malignant neoplasms. Patient 1 developed an embryonal rhabdomyosarcoma (RMS) and a choroid plexus carcinoma (CPC), while patient 2 developed a CPC and subsequently presented with both an osteosarcoma (OS) and renal cell carcinoma (RCC). We utilized DNA sequence analysis and immunohistochemistry to determine p53 gene status in the germline and tumors, as well as evidence for SV40 T-antigen oncoprotein expression. Each patient harbored a heterozygous germline p53 mutation at codons 175 and 273, respectively. In patient 1, the normal p53 gene was lost while the mutant p53 allele was reduced to homozygosity in the RMS. Both normal and mutant genes were maintained in the CPC. In patient 2, normal and mutant p53 alleles were retained in both the CPC and RCC. Both specific PCR and immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addition to chromosomal alterations, epigenetic mechanisms may disrupt p53 function during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the normal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetically susceptible individuals.
Publication types
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Case Reports
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Polyomavirus Transforming / genetics
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Antigens, Polyomavirus Transforming / metabolism*
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Carcinoma / genetics
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Carcinoma / metabolism
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Carcinoma / virology
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Carcinoma, Renal Cell / genetics
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Carcinoma, Renal Cell / metabolism
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Carcinoma, Renal Cell / virology
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Cell Transformation, Neoplastic
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Cell Transformation, Viral*
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Choroid Plexus Neoplasms / genetics
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Choroid Plexus Neoplasms / metabolism
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Choroid Plexus Neoplasms / virology
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Codon / genetics
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DNA, Neoplasm / genetics*
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DNA, Viral / genetics
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DNA, Viral / isolation & purification*
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Facial Neoplasms / genetics
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Facial Neoplasms / metabolism
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Facial Neoplasms / virology
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Fatal Outcome
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Female
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Gene Expression Regulation, Neoplastic*
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Genes, p53
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Genetic Predisposition to Disease
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Humans
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Infant
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Kidney Neoplasms / genetics
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Kidney Neoplasms / metabolism
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Kidney Neoplasms / virology
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Li-Fraumeni Syndrome / genetics
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Li-Fraumeni Syndrome / metabolism
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Li-Fraumeni Syndrome / virology*
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Male
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Organ Specificity
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Osteosarcoma / genetics
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Osteosarcoma / metabolism
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Osteosarcoma / virology
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Papillomavirus Infections / genetics
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Papillomavirus Infections / metabolism
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Papillomavirus Infections / virology*
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Pedigree
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Polymerase Chain Reaction
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Polymorphism, Single-Stranded Conformational
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Reproducibility of Results
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Rhabdomyosarcoma / genetics
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Rhabdomyosarcoma / metabolism
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Rhabdomyosarcoma / virology
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Simian virus 40 / genetics
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Simian virus 40 / isolation & purification
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Simian virus 40 / physiology*
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Skull Neoplasms / genetics
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Skull Neoplasms / metabolism
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Skull Neoplasms / virology
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Temporal Bone
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / deficiency
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Tumor Suppressor Protein p53 / metabolism
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Tumor Virus Infections / genetics
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Tumor Virus Infections / metabolism
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Tumor Virus Infections / virology*
Substances
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Antigens, Polyomavirus Transforming
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Codon
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DNA, Neoplasm
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DNA, Viral
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Neoplasm Proteins
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Tumor Suppressor Protein p53