Showing papers by "Michael R. Stratton published in 1995"

Germline mutations of the BRCA1 gene in breast and ovarian cancer families provide evidence for a genotype-phenotype correlation.

Abstract: Mutations in the BRCA1 gene, discovered in 1994, are associated with an 80-90% lifetime risk of breast cancer. We have analysed 60 families with a history of breast and/or ovarian cancer for germline mutations in BRCA1. Twenty-two different mutations were detected in 32 families (53%), of which 14 are previously unreported. We observed a significant correlation between the location of the mutation in the gene and the ratio of breast to ovarian cancer incidence within each family. Our data suggest a transition in risk such that mutations in the 3' third of the gene are associated with a lower proportion of ovarian cancer. Haplotype analysis supports previous data which suggest some BRCA1 mutation carriers have common ancestors; however, we have found at least two examples where recurrent mutations appear to have arisen independently.

A Collaborative Survey of 80 Mutations in the BRCA1 Breast and Ovarian Cancer Susceptibility Gene: Implications for Presymptomatic Testing and Screening

Abstract: Objectives. —To report the initial experience of an international group of investigators in identifying mutations in theBRCA1breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations. Design. —Nine laboratories in North America and the United Kingdom tested forBRCA 1mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples. Participants. —A total of 1086 women with either breast or ovarian cancer. Main Outcome Measure. —The detection of sequence variation in patients' DNA samples that is not found in sets of control samples. Results. —BRCA 1mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of theBRCA 1gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening. Conclusions. —The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test forBRCA 1mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations. (JAMA. 1995;273:535-541)

Atypical ductal hyperplasia of the breast: clonal proliferation with loss of heterozygosity on chromosomes 16q and 17p.

Abstract: AIMS--To determine if allelic loss on chromosomes 16q and 17p, commonly encountered in in situ and invasive ductal carcinomas, is present in atypical ductal hyperplasia (ADH); to determine whether ADH is a neoplastic (clonal) or hyperplastic (polyclonal) proliferation. METHODS--Fourteen cases of ADH were examined for allele loss at loci on chromosome 16q and 17p using a microdissection technique, polymorphic DNA markers and the polymerase chain reaction (PCR). RESULTS--Loss of heterozygosity (LOH) was detected in five of nine informative cases on chromosome 16q at the microsatellite D16S413 and two of eight informative cases on chromosome 17p at D17S796. CONCLUSIONS--The incidence of LOH at these loci is similar to that previously observed in ductal carcinoma in situ and in invasive ductal carcinoma. Because of the nature of the technique used, our findings also demonstrate that ADH is a monoclonal, and hence, neoplastic proliferation rather than a hyperplastic (polyclonal) condition as its name suggests. There is thus a case for including ADH, as presently defined, within the spectrum of ductal carcinoma in situ.

Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12-q13: evidence for its role as a tumour suppressor gene.

Abstract: The human skin is a complex organ composed of the surface epidermis, the subjacent dermis (in which blood vessels, lymphatics and nerves are located) and the skin appendages. The latter include hair follicles, sebaceous glands (which secrete lipids that may serve as a permeability barrier, emollient or antimicrobial agent), apocrine glands (which secrete scents) and eccrine glands (which produce sweat for temperature control). Hereditary cylindromatosis (MIM 123850) is a rare autosomal dominant disease characterised by the development of multiple neoplasms originating from the skin appendages. These neoplasms have been termed cylindromas due to their characteristic microscopic architecture and are believed to exhibit apocrine or eccrine differentiation. We have carried out a genome search using two families with this disease, which has provided strong evidence for linkage of cylindromatosis to loci on chromosome 16q12-q13. Using markers close to the cylindromatosis gene, consistent loss of the wild-type allele was observed in 19 tumours from four individuals in the two families, indicating that the gene is likely to be a tumour suppressor gene.

Loss of heterozygosity in ductal carcinoma in situ of the breast.

Abstract: Loss of heterozygosity (LOH) at loci reported to show allele loss in invasive breast cancers was examined in ductal in situ carcinomas of the breast using polymorphic short tandem repeats and the polymerase chain reaction (PCR). LOH was detected at all loci examined in at least 11 per cent of the samples examined. The proportion of cases of in situ carcinoma showing LOH at these loci was similar to that previously reported in invasive cancers. Cases of pure in situ cancer without an invasive component exhibited an overall lower frequency of allele loss. LOH at more than one locus was observed in some intraductal cancers. In a small number of cases, LOH was present in the invasive but not in the intraductal component of the tumour, suggesting that mutation at the locus concerned was associated with development of invasive behaviour.

Mutations in the p53 gene in schistosomal bladder cancer: a study of 92 tumours from Egyptian patients and a comparison between mutational spectra from schistosomal and non-schistosomal urothelial tumours.

Abstract: Much of bladder cancer in East Africa and the Middle East is attributed to chronic urinary infection with Schistosoma haematobium ('schistosomiasis'). Most schistosomal bladder cancer (SBC) is squamous cell carcinoma (SCC) and occurs in the fifth decade of life. In contrast, nonschistosomal bladder cancer (NSBC) in Western countries usually occurs in the seventh decade of life and is largely transitional cell carcinoma (TCC). To shed light on the mechanisms underlying these different patterns of bladder cancer we looked for mutations in the p53 gene in SBC from 92 patients in Egypt, where schistosomiasis is hyperendemic. Patients' mean age at presentation of bladder cancer was 49.4 +/- 9.9 years and 90% had a clinical history of schistosomiasis and/or histological evidence of schistosomal eggs adjacent to the carcinoma. There were 53 SCC, 23 TCC, 13 adenocarcinomas and three other carcinomas. Thirty patients had tumours with mutations in exons 5-8 of the p53 gene: 17/53 SCC, 8/23 TCC, 4/13 adenocarcinomas and 1/3 other tumours. Of 19 mutations in SCC, 16 were base pair substitutions (BPS), two were deletions and one an insertion. Two tumours each contained two mutations. Of the BPS, nine were transitions at CpG dinucleotides and two were G-->T transversions. All the mutations in TCC were BPS: four were transitions at CpG dinucleotides and three were G-->C transversions. One TCC had two mutations. Of four adenocarcinomas with mutations, two had transitions at CpG dinucleotides. Of the 30 BPS mutations, 16 were transitions at CpG dinucleotides, of which 12 were C-->T. We combined these 33 mutations with six obtained from Egyptian SCC reported by Habuchi et al. (Cancer Res., 53, 3795-3799, 1993) to compile a mutational spectrum. This was compared with a NSBC spectrum assembled from 118 mutations reported in the literature. The proportion of BPS at CpG dinucleotides was significantly higher in SBC than in NSBC (18/34 versus 25/103, P = 0.003). There was also a bias away from mutations in exons 7 and 8 towards mutations in exons 5 and 6. We suggest that the excess of transitions at CpG dinucleotides in SBC results from nitric oxide (NO) produced by the inflammatory response provoked by schistosomal eggs. NO could produce such mutations directly, by deamination of 5-methylcytosine, and indirectly, following conversion to nitrate, bacterial reduction to nitrite and endogenous formation of urinary N-nitroso compounds. These produce O6-alkylguanines in DNA, leading to very high rates of G:C-->A:T transitions, a process possibly augmented by inefficient repair of alkylated bases at CpG dinucleotides.

Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13.

Abstract: Loss of heterozygosity (LOH) on chromosome 13 occurs on 25-30% of breast tumours. This may reflect the inactivation of the retinoblastoma susceptibility gene RB1. However, recently another candidate tumour-suppressor gene has been identified on chromosome 13 by linkage analysis, the breast cancer susceptibility gene BRCA2. To investigate the involvement of BRCA2 in sporadic breast cancer 200 breast tumours were tested for LOH on chromosome band 13q12-q14, using 11 highly polymorphic microsatellite markers. LOH was found in 65 tumours, which all showed simultaneously loss of BRCA2 and RB1. Of 12 breast tumour cell lines tested with polymorphic microsatellite markers, seven showed a contiguous region of homozygosity on 13q12-q14, suggesting LOH in the tumour from which the cell line had been derived. One cell line showed homozygosity in the BRCA2 region and heterozygosity at RB1. This is the only indication that BRCA2 is a distinct target for LOH on chromosome 13 in addition to RB1.

Loss of heterozygosity in lobular carcinoma in situ of the breast.

Abstract: Aims—(1) To investigate whether loss of heterozygosity identified at various loci in invasive breast carcinoma or is present in lobular carcinoma in situ (LCIS). (2) To investigate whether LCIS is a monoclonal (neoplastic) or a polyclonal (hyperplastic) proliferation. Methods—Forty three cases of LCIS (30 with associated invasive carcinoma or in situ ductal carcinoma (DCIS) and 13 cases of pure LCIS) were investigated for loss of heterozygosity on chromosomes 16q, 17q, 17p, and 13q using a microdissection technique, polymorphic DNA markers, and the polymerase chain reaction (PCR). Results—Loss of heterozygosity was detected in both subgroups of LCIS at all the loci examined. There was no significant difference in the frequency of the loss between the group associated with invasive carcinoma and the pure LCIS group. The frequency of loss of heterozygosity ranged from 8% on 17p to 50% on 17q. Conclusions—Because of the nature of the technique employed, our findings show that LCIS is a monoclonal (neoplastic) proliferation rather than a hyperplastic proliferation. The incidence of loss of heterozygosity on 17p (D17S796) is lower than we have observed previously in DCIS, suggesting that LCIS and DCIS are different genetically as well as clinically and morphologically. The similar incidence of loss of heterozygosity on 16q and 17q, however, suggests that DCIS and LCIS may share a common pathway of evolution.