Tissue-specific expression of SV40 in tumors associated with the Li-Fraumeni syndrome

Inactivation of wild-type p53 tumor suppressor function is the primary mech anism of tumor initiation in Li-Fraumeni syndrome (LFS) individuals with ge rmline p53 mutations. Tumors derived from LFS patients frequently retain th e normal p53 allele, suggesting that alternative mechanisms in addition to gene deletion must be involved in inactivating wild-type p53 protein. DNA t umor viruses, such as SV40, target p53 for inactivation through the action of viral oncoproteins. We studied the probands from two unrelated LFS famil ies, each of whom presented with multiple malignant neoplasms. Patient 1 de veloped 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 seque nce analysis and immunohistochemistry to determine p53 gene status in the g ermline and tumors, as well as evidence for SV40 T-antigen oncoprotein expr ession. Each patient harbored a heterozygous germline p53 mutation at codon s 175 and 273, respectively. In patient 1, the normal p53 gene was lost whi le the mutant p53 allele was reduced to homozygosity in the RMS. Both norma l and mutant genes were maintained in the CPC. In patient 2, normal and mut ant p53 alleles were retained in both the CPC and RCC. Both specific PCR an d immunostaining detected SV40 T-antigen in both CPCs and the RCC. In addit ion to chromosomal alterations, epigenetic mechanisms may disrupt p53 funct ion during tumorigenesis. In two LFS patients, we found SV40 DNA sequences and viral T-antigen expression that could account for inactivation of the n ormal p53 protein. Inactivation of p53 or other tumor suppressors by viral proteins may contribute to tumor formation in specific tissues of genetical ly susceptible individuals.