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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 (Δ133p53). 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.