Search

Researchers have identified mutations in the BRCA1 gene predisposing women to breast cancer that would not be detected by many tests. Genetic analysis performed on 798 people from families thought to have an increased risk of BRCA1 mutations found that 13% of the women had a mutation that increased their risk of breast cancer. The women had one of 48 different mutations, 24 of which have not been previously reported. Two-thirds of the previously unknown mutations occurred in other parts of the BRCA1 gene than exon 11, which is the part most researchers focus on. Consequently, tests based on exon 11 would miss 33% of the mutations in non-Ashkenazi women., Context.--A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. Objectives.--To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. Design.--A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. Participants.--Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. Major Outcome Measures.--Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. Results.--In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (uni-lateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. Conclusions.--Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range,of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice. JAMA. 1997;278:1242-1250

Many of the mutations identified in the BRCA1 gene may result in a truncated protein product and three BRCA1 gene mutations may occur more often than others. Women who have a mutation in the BRCA1 gene are predisposed to breast and ovarian cancer. Researchers in nine laboratories in North America and the United Kingdom took blood or tumor samples from 1,086 women with breast or ovarian cancer to test the patients' DNA for BRCA1 gene mutations. DNA samples from 63 women contained a total of 38 unique mutations. Of these, most were frameshift mutations that are caused by the insertion or deletion of at least one nucleotide. This type of mutation can affect protein translation most often through premature truncation of the protein product. The mutations were distributed throughout many regions of the BRCA1 gene. Three common BRCA1 mutations accounted for 32% of the mutations identified in the DNA from 63 families., Objectives. - To report the initial experience of an international group of investigator's in identifying mutations in the BRCA1 breast 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 for BRCA1 mutations 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. - BRCA1 mutations 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 the BRCA1 gene. 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 for BRCA1 mutations. 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.