Does a genotoxic carcinogen contribute to human breast cancer? The value of mutational spectra in unravelling the aetiology 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Section of Molecular Carcinogenesis, Institute of Cancer Research, Sutton, Surrey, UK.
P J
PJ
Biggs
W
W
Warren
S
S
Venitt
M R
MR
Stratton
D001943:Breast Neoplasms / Q000209:etiology* / Q000235:genetics; D002273:Carcinogens; D015179:Colorectal Neoplasms / Q000235:genetics; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D016158:Genes, p53; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D009153:Mutagens
D002273:Carcinogens; D004273:DNA, Neoplasm; D009153:Mutagens