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ABSTRACT: A novel approach to mutation screening in the large exon 11 (comprising 3427 bp) of the human BRCA1 gene is presented. Restriction endonuclease fingerprinting single-strand conformation polymorphism (REF-SSCP) is based on repeated detection of DNA sequence variants in different restriction endonuclease fragments, and we evaluated the method using blood samples from 25 Norwegian patients with hereditary breast/ovarian cancer. We compared REF-SSCP to constant denaturant gel electrophoresis (CDGE) and to the protein truncation test (PTT). REF-SSCP detected 12 different DNA variants. Four of these were not detected by CDGE, and only one variant detected by CDGE was missed by REF-SSCP. PTT detected 4 of these 13 variants. REF-SSCP was subsequently applied to a second patient series (Swedish, n=20). A total of 14 different DNA variants were detected by REF-SSCP, 6 of which were truncating mutations (PTT detected only 4). Nonsense and frameshift mutations that are putative breast/ovarian cancer mutations, were detected in 7 of the 25 Norwegian and 9 of the 20 Swedish patients.
Journal of Molecular Medicine 11/2000; 78(10):580-587. · 4.67 Impact Factor
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Journal of Molecular Medicine 11/2000; 78:580-587. · 4.67 Impact Factor
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ABSTRACT: Germline mutations in the BRCA1 gene predispose to breast and ovarian cancer. An estimated 45% of families with multiple breast cancer cases and more than 80% of breast-ovarian cancer families are linked to BRCA1. Mutation analyses by collaborative laboratories have revealed around 460 distinct BRCA1 sequence alterations, mostly germline mutations from familial cases. The majority of these alterations were nonsense and frame-shift mutations. In the present study, breast tumors of both sporadic and familial origin were investigated for allelic imbalance (AI) at the BRCA1 locus. AI was observed in 52% of the sporadic cases and in 17% of the familial cases. Furthermore, 104 breast carcinomas from patients with sporadic disease and 77 patients with positive family histories of breast and/or ovarian cancer were examined for translation-terminating mutations in exon 11 of the BRCA1 gene using the protein truncation test (PTT). No somatic mutations were detected in any of the tumors analysed, and only one BRCA1 mutation carrier was found among the familial cases. The result of this study gives no indication that truncating somatic mutations in exon 11 of BRCA1 play a major role in the tumorigenesis of the breast. Furthermore, the frequency of such mutation carriers in breast cancer populations with weak family histories of breast and/or ovarian cancer seems to be low.
Breast Cancer Research and Treatment 01/1998; 48(3):259-264. · 4.43 Impact Factor
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ABSTRACT: Two genes predisposing females to autosomal dominant breast cancer are located on chromosome 17. Mutations in the p53-gene on the short arm have been shown to predispose females to early onset breast cancer in families with the rare Li-Fraumeni syndrome. Another locus on 17q (BRCA1), was found to be linked to the disease in a subset of families with breast cancer. In order to determine the involvement of tumour suppressor genes at these loci in tumour development, we studied allele losses for markers on chromosome 17 in 78 familial breast carcinomas. The analysis used six polymorphic DNA markers, three on each arm. We found support for at least four separate regions displaying allele losses on chromosome 17: the p53-region, the distal part of 17p, the BRCA1 region and the distal part of 17q. The frequency of allele losses on distal 17p (16%) is low in these familial tumours compared with the previously reported incidence in sporadic tumours (>50%), whereas the frequency of losses at the p53 locus and on 17q was similar to sporadic tumours (5%–40%). These data suggest that several regions on chromosomal 17 can harbour tumour suppressor genes involved in tumour development of familial breast cancer.
Human Genetics 02/1993; 91(1):6-12. · 5.07 Impact Factor
