Csilla I. Szabo

Prevalence of founder BRCA1 and BRCA2 mutations among breast and ovarian cancer patients in Hungary

We have investigated the impact of BRCA1 and BRCA2 mutations that were frequently identified among Hungarian high‐risk breast‐ovarian cancer families (Ramus et al., 1997b , AJHG), on the development of breast and ovarian cancer in the general Hungarian population. The prevalence of 3 BRCA1 mutations (185delAG, 300T→G and 5382insC) and 2 BRCA2 mutations (6174delT and 9326insA) was evaluated in a hospital‐based consecutive series of 500 female breast cancer patients and 90 ovarian cancer patients, not selected for age at diagnosis or family history of cancer, as well as in 350 controls. Among breast cancer patients, 3.6% (18/500) carried a founder mutation: 9 BRCA1 300T→G, 7 BRCA1 5382insC, 1 BRCA1 185delAG and 1 BRCA2 9326insA. Among ovarian cancer patients, 11% (10/90) carried a founder mutation: 5 BRCA1 185delAG, 4 BRCA1 300T→G and 1 BRCA1 5382insC. One control carried a mutation, BRCA1 5382insC. Inherited breast cancer was more frequent among women with younger age at diagnosis: 6.1% of women younger than age 50 but 2.4% of women diagnosed at age 50 or older carried one of the founder mutations. There was no association between mutation status and age at diagnosis of ovarian cancer. Three of 23 medullary breast cancers were inherited (p = 0.038). Carrier status was also associated with a non‐significant trend toward advanced tumor stage at diagnosis. These mutations could be evaluated among all ovarian cancer patients and breast cancer patients younger than age 60 and of Hungarian ancestry. Int. J. Cancer 86:737–740, 2000.

22 genes from chromosome 17q21: cloning, sequencing, and characterization of mutations in breast cancer families and tumors

In our effort to identify BRCA1, 22 genes were cloned from a 1-Mb region of chromosome 17q21 defined by meiotic recombinants in families with inherited breast and/or ovarian cancer. Subsequent discovery of another meiotic recombinant narrowed the region to approximately 650 kb. Genes were cloned from fibroblast and ovarian cDNA libraries by direct screening with YACs and cosmids. The more than 400 cDNA clones so identified were mapped to cosmids, YACs, and P1 clones and to a chromosome 17 somatic panel informative for the BRCA1 region. Clones that mapped back to the region were hybridized to each other and consolidated into clusters reflecting 22 genes. Ten genes were known human genes, 5 were human homologs of known genes, and 7 were novel. Each gene was sequenced, compared to genes in the databases to find homologies, and analyzed for mutations in BRCA1-linked families and tumors. Eight mutations were found in tumors or families and not in controls. In the gene encoding alpha-N-acetylglucosaminidase, approximately 100 kb proximal to the 650-kb linked region, somatic nonsense, missense, and splice junction mutations occurred in 3 breast tumors, but not in these patients germline DNA nor in controls. In an ets-related oncogene in the linked region, a missense mutation cosegregated with breast cancer in one family and was not observed in controls. In a human homolog of a yeast pre-mRNA splicing factor, 3 different mutations cosegregated with breast cancer in 3 families and were not observed in controls. In these and the other genes in the region, 36 polymorphic variants were observed in both cases and controls.

Evidence for a BRCA1 Founder Mutation in Families of West African Ancestry

This study was supported by National Institutes of Health grants CA27632, CA55772, and RR03048, by U.S. Department of Defense grant 17-94-J4245, and by grants from the Komen Foundation and the Sylvester Comprehensive Cancer Center Developmental Program.

Genetic markers for breast and ovarian cancer

Specific BRCA1 mutations, PCR primers and hybridization probes are used in nucleic acid-based methods for diagnostic of inheritable breast cancer susceptibility. Addtionally, binding agents, such as antibodies, specific for peptides encoded by the subject BRCA1 mutants are used to identify expression products of diagnostic mutations/rare alleles in patient derived fluid or tissue samples. Compositions with high binding affinity for transcription or translation products of the disclosed BRCA1 mutations and alleles are used in therapeutic intervention. Such products include anti-sense nucleic acids, peptides encoded by the subject nucleic acids, and binding agents such as antibodies, specific for such peptides.