ABSTRACT: 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.
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.
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.
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.
Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations.
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 (unilateral 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.
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 The Journal of the American Medical Association 11/1997; 278(15):1242-50. · 30.03 Impact Factor
ABSTRACT: MTS-1 is a candidate tumor suppressor gene on chromosome 9p21-22, a region frequently observed to have loss of heterozygosity in esophagus squamous cell carcinomas and pancreatic ductal adenocarcinomas. In order to determine whether MTS-1 sequences are deleted or mutated in cell lines derived from these cancers, we performed PCR amplification of MTS-1 exons 1 and 2. In this fashion, we found that 67% of esophagus squamous cancer cell lines have deletions of both exons 1 and 2, and 50% of pancreatic cancer cell lines have similar deletions. Furthermore, an additional 30% of pancreatic cancer cell lines harbored point mutations or microdeletions based on DNA sequencing. MTS-1 encodes p16, an inhibitor of cyclin-dependent kinase 4 (cdk4) which complexes with cyclin D1. Our data suggest that MTS-1 deletions and mutations may play an important role in the molecular pathogenesis of esophagus squamous cell and pancreatic cancers.
Oncogene 03/1995; 10(3):619-22. · 6.37 Impact Factor
Journal of American Medical Association. 01/1995; 273:535-541.