DOES A GENOTOXIC CARCINOGEN CONTRIBUTE TO HUMAN BREAST-CANCER - THE VALUE OF MUTATIONAL SPECTRA IN UNRAVELING THE ETIOLOGY OF CANCER

The p53 tumour suppressor gene is turning out to be a useful reporter for the stigmata of past genotoxic exposure. About half of all human cancers contain p53 mutations most of which occur in those regions (exons 5 - 8) of the gene that are highly conserved during evolution. Mutations are mainly of the missense type and their frequency and distribution vary among different kinds of cancer. The ability to detect all six possible base-substitution mutations in the p53 gene in human tumours makes it possible to construct mutational spectra for different cancers at a locus clearly implicated in carcinogenesis. Transitions at one particular hotspot-the CpG dinucleotide-occur frequently in many cancers and may reflect endogenous mutation. A reduction in the proportion of CpG mutations at the expense, for example, of an increase in GC to TA transversions may signal the effect of an exogenous mutagen. We exploited these features of the p53 gene to examine the evidence that a previously unsuspected genotoxic exposure may contribute to the high incidence of breast cancer in women living in rich industrialized countries. We compiled a mutational spectrum of p53 from 120 breast cancers and compared it with the spectrum from 145 colorectal cancers and 246 lung cancers. A germline p53 spectrum was constructed using data from 27 patients. Two hundred germline mutations in the haemophilia B gene served as a 'background' spectrum. The spectrum of mutations in the p53 gene in breast cancer revealed a reduction in the proportion of G-->A and C-->T transitions at CpG dinucleotides compared with colorectal cancer (P < 0.0005) and an increase in G-->T transversions (P < 0.0005). Other mutations showed no significant differences from colorectal cancer or germline mutational spectra. In breast cancer, as in lung cancer, G-->T transversions were over-represented at CpG dinucleotides and there was also a G-->T hotspot at codon 157 that was not seen in colorectal cancer. Moreover, G-->T transversions were much more common on the coding strand, as in lung cancer. Thus, the mutational spectrum in the p53 gene of breast cancer differs significantly from that thought to be attributable to endogenous or background mutagenic processes. It resembles more closely the lung cancer spectrum, which is probably caused by exogenous mutagenic chemicals. These findings pose the following questions. Is a mutagenic agent of exogenous or endogenous origin involved in the aetiology of breast cancer? Is the breast epithelium and/or its neoplastic derivatives less efficient at repairing DNA damage than are colorectal epithelial cells?