BRCA1 mutations and polymorphisms in a population-based registry of ovarian cancer.

摘要

Ovarian cancer accounts for 4% of cancer cases and 5% of cancer deaths among US women. A better knowledge of the fundamental causes may lead to improvements in prevention, early detection, and treatment. Inherited mutations in the tumor suppressor gene BRCA1 are estimated to initiate 5% of ovarian cancer cases. Pedigree information, epidemiological data, and biological specimens were collected from women enrolled in the Family Registry of Ovarian Cancer, a multiethnic population based series of patients with epithelial ovarian cancer and their relatives. Blood samples from patients and their affected and unaffected family members were collected and DNA was isolated. DNA from patients and family members were screened for genetic alterations in BRCA1 by single-stranded DNA conformation polymorphism analysis. If an alteration was detected, the sample was sequenced to determine the exact change.; DNA samples from 412 ovarian cancer cases were analyzed. Twenty-eight mutations were detected including 18 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 1 in-frame deletion of 15 base pairs, and 1 splice-site mutation. Fifteen polymorphisms, ten of which are common, and 26 rare unclassified variants were also detected.; RT-PCR analysis demonstrated that a splice-site mutation (IVS 23 + 1G/A) found in DNA of a patient caused a deletion of exon 23 in mRNA, predicting a frameshift and a truncated protein.; Two unclassified variants, V 1804 D and M1628 T, were found in different cases. Site-directed mutagenesis of full length, wild type BRCA1 expression vector was used to create the missense variants, V 1804 D and M 1628 T. The mutant, V 1804 D, which lies in the BRCT domain, was shown to inactivate BRCA1 dependent activation of a p53-activated promoter, while M 1628 T, which lies just upstream of the BRCT domain did not.; We studied the prevalence of BRCA1 alterations in family history positive and negative cases among ethnic groups and made correlations with respect to type and site of alterations and ethnicity, age of onset of disease, and tumor type. Ashkenazi Jewish women have the greatest incidence of BRCA1 related ovarian cancer, while non-white women have a low prevalence of BRCA1 mutations. BRCA1 mutations were found to be more prevalent in women with early age disease. Also, mutations in BRCA1 are more prevalent in women with a family history of disease, than in women without a family history. No mutations in BRCA1 were found in women mucinous tumors. Germline mutations in BRCA1 were found in women with borderline tumors and therefore borderline tumors should be included in BRCA1 syndrome. These correlations will help to identify who is at increased risk for developing ovarian cancer.