Analysis of germline p53 mutations in
breast cancer reveals that the Li-Fraumeni and Li-Fraumeni-like syndromes are mostly related to the loss of
initiation codon 133 of regulatory TP53
isoforms (Delta133p53). In eight
codons of exons 5-8 (including 133), mutations are frequent in Li-Fraumeni-related, but scarce in sporadic
breast cancer, while in six more
codons they are frequent both in familial and sporadic breast
cancers. At the proximity of these
codons, we observed in somatic mutation databases, 16
codons (minihotspots mostly in exons 7, 8) which undergo frequent G:C > A:T transitions (non-CpG) in all sporadic
cancers. In addition, in sporadic
breast cancer we observed 35 adjacent
codons in which the following types of mutation are observed: frequent G:C > A:T transitions at CCs/GGs, frequent silent mutations in exons 5,6 and suppressed
nonsense mutations (5
codons, few records). Non-CpG G:C > A:T transitions in the 35
codons are rare in familial
cancers (p53, BRCA1, or BRCA2-related), but frequent in sporadic
cancers in organs where Li-Fraumeni-related
carcinogenesis is common e.g. adrenal cortex, soft tissues. These data are in support of the following tissue-specific processes: in sporadic
breast cancer (
sarcomas etc.), loss of methylation sites (in 35
codons mostly next to
codon 133), might lead to loss of silencing of TP53
isoforms which are suppressed in these tissues. On the contrary, "spreading" of
cytosine methylation (asymmetric) in a G:C-rich region next to common hotspots (
codons 238-252 in minihotspots) and mutagenesis probably destabilizes all tissues. Frequent C > T activation at non-CpG is also observed in prostate sporadic
cancer, which similarly to breast, undergoes age-related crisis. The above data reveal that tissue-specific epigenetic regulatory mechanisms might be involved in p53 instability.