Showing papers by "Michael R. Stratton published in 1993"

Does a genotoxic carcinogen contribute to human breast cancer ? The value of mutational spectra in unravelling the aetiology of cancer

Abstract: 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)

Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings

Abstract: We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.

Absence of linkage to the ataxia telangiectasia locus in familial breast cancer.

Abstract: Heterozygotes for ataxia-telangiectasia (AT) are known to have an increased risk of breast cancer. The gene (or genes) responsible for almost all cases of AT has been localised to chromosome 11q by genetic linkage analysis. To examine the possibility that AT heterozygosity may account for a substantial proportion of familial breast cancer, we have typed five markers on chromosome 11q in 16 breast cancer families. We have found no evidence for linkage between breast cancer and chromosome 11q markers and conclude that the contribution of AT to familial breast cancer is likely to be minimal.