Variations in the p53 Gene

Several DNA sequence variants (polymorphisms) present in human populations have been discovered, only two of which alter the amino acid sequence of the p53 protein (Buchman et al., 1988 Felley-Bosco et al., 1993 Gerwin et al., 1992 Matlashewski et al., 1987) (Table HI). Most polymorphism are localized in introns, at sites that are not splice or branch sites. So far, there is no clear evidence of increased cancer linked to a sequence polymorphism that leaves the p53 protein unaltered (Table IIIA). Theo- 

Polymorphisms in the p53 coding sequence that do not alter the amino acid sequence  

Among the human tumor mutations identified by sequencing, 87.2% are single base substitutions and 12.8% are complex mutations and short deletions or insertions. Missense mutations have been observed at 231 of the 393 codons, including all the codons of the DNA-binding domain except codon 123. This codon (ATC, threonine) is well conserved in evolution, but experimental mutation (to Alanine) at this codon has been shown to activate, rather than suppress DNA-binding activity (Freeman et al., 1994). The vast majority of the mutated codons are recurrent mutation sites that are likely to result in dysfunctional p53. Silent mutations represent up to 3.9% of the mutations in the database and it is possible that mutations occurring at rare 

Approximately half of the families with the Li-Fraumeni cancer syndrome carry one mutant p53 allele in somatic cells (Malkin et al., 1990 Srivastava et al., 1990 see review in Kleihues et al., 1997). This disease is characterized by familial clustering of various cancers, particularly early-onset breast cancer, sarcomas, leukemias, and brain and adrenocortical tumors. Mice with targeted nonfunctional p53 alleles provide an experimental model for this disorder. Early spontaneous tumors, primarily lymphomas and sarcomas, arise frequently in p53 / and p53+/ mice, reflecting the Li-Fraumeni syndrome in these respects. Curiously, mammary and brain tumors are uncommon in p53 knockout mice (Donehower, 1996b Eng et al., 1997). 

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