Lessons from TP53mutations in breast cancers: from carcinogen fingerprints to clinical correlates

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About 1000 mutations in breast cancers are listed in the IARC TP53 mutation database [1]. Overall, the mutation prevalence is relatively low (20-30%). Mutations are associated with most aggressive tumor types and carry a significant risk of bad prognosis and outcome in both node-positive and node-negative tumors. Among tumors expressing mutant p53, those with mutations in the L2/L3 loops of the protein (DNA-binding surface) have a poorer response to some forms of treatment than tumors with mutations at other sites [2]. It is noteworthy that p53 protein levels are elevated in more than 50% of breast cancers, suggesting that p53 function may be deregulated by mechanisms other than mutation.

The pattern of TP53 mutations shows a relatively high prevalence of insertions, deletions and nonsense mutations (altogether, 25%). The most frequent mutation type is GC to AT transitions (40%), equally affecting CpG and non-CpG sites. Cohort comparisons have shown differences in the nature, localization and frequency of mutations, but these studies need to be substantiated on larger groups [3].

Breast cancer frequently arises in Li-Fraumeni families [4]. The mutations found in this context may be considered as representative of spontaneous mutations arising in breast cancer. Comparison with sporadic cancer shows that two transversions, G to T and G to C, are not found in Li-Fraumeni breast cancer patients. These transversions represent 18% of somatic breast-cancer mutations. They show a strong strand bias and occur at sites often mutated in lung cancers from smokers (codons 157, 248, 249 and 273) or in bladder cancers from smokers and/or dye-exposed workers (codons 158 and 280). Overall, these data indicate that although most of breast cancer mutations probably have a spontaneous origin, a small proportion of mutations show signatures that suggest the involvement of exogenous carcinogens.