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. © 2000 Wiley‐Liss, Inc.

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Germline mutations in the BRCA1 and BRCA2 genes account for the majority of high‐risk breast/ovarian cancer families, depending on the population studied. Previously, BRCA1 mutations were described in women from Western Poland. To further characterize the spectrum of BRCA1 mutations and the impact of BRCA2 mutations in Poland, we have analyzed 25 high‐risk breast and/or ovarian cancer families from North‐Eastern Poland for mutations in all coding exons of the BRCA1 and BRCA2 genes, using combined heteroduplex analysis/SSCP followed by direct DNA sequence analysis. Out of 25 probands a total of five (20%) carried three recurrent BRCA1 mutations (300T>G, 3819del5, 5382insC). The 300T>G mutation accounted for 60% (3/5) of BRCA1 mutations and allelotyping suggested a common founder of this mutation. No unique mutations were found. In addition, we identified three BRCA2 (12%) mutations, one recurrent 4075delGT, and two novel frameshift mutations, 7327ins/dupl19 and 9068delA. We conclude that 30% of high‐risk families from North‐Eastern Poland may be due to recurrent BRCA1 and unique BRCA2 mutations. Intriguingly, the BRCA1 mutation spectrum seems to be different within subregions of Poland. Hum Mutat 15:480–481, 2000. © 2000 Wiley‐Liss, Inc.

The BRCA1 Exon 13 Duplication Screening Group * Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report. Methods used to screen for mutations in the BRCA1 gene (MIM 113705) focus mainly on genomic DNA, and, being PCR based, they do not enable the detection of large DNA rearrangements. This may explain why only 12 large germline insertions or deletions have been described (

Genetic alterations of chromosome 17 have been reported to occur frequently both in human sporadic and familial malignancies. The present study was undertaken to explore the possible involvement of chromosome 17 genes including TP53 and the breast cancer susceptibility sarcoma. Fifteen patients were screened by polymerase chain reaction (PCR) for loss of heterozygosity (LOH) using four highly polymorphic markers. Loss of heterozygosity at the TP53 locus was detected in 40% (6/15) of informative cases while it was 14% (2/14) at the locus of thyroid hormone receptor alpha (THRA1), 21% (3/14) at the D17S855 locus intragenic to BRCA1 and 27% (4/15) at the D17S579 locus. In 53% of the cases studied at least one locus on chromosome 17 was affected by LOH. In our panel, the overall LOH frequency on 17p and 17q was observed to be 40% (6/15) and 27% (4/15), respectively. Comparison of LOH frequencies with clinical and prognostic features revealed significant correlation only with tumor recurrence. Our results confirm that the role of the TP53 tumor suppressor gene is important in the pathogenesis of sporadic osteosarcoma and suggest that 17q12-21 region abnormalities may be involved in the development and/or progression of this tumor.