RESUMO
To date, more than 300 distinct small deletions, insertions and point mutations, mostly leading to premature termination of translation, have been reported in the breast/ovarian-cancer susceptibility gene BRCA1. The elevated frequencies of some mutations in certain ethnic subpopulations are caused by founder effects, rather than by mutation hotspots. Here we report that the currently available mutation spectrum of BRCA1 has been biased by PCR-based mutation-screening methods, such as SSCP, the protein truncation test (PTT) and direct sequencing, using genomic DNA as template. Three large genomic deletions that are not detected by these approaches comprise 36% of all BRCA1 mutations found in Dutch breast-cancer families to date. A 510-bp Alu-mediated deletion comprising exon 22 was found in 8 of 170 breast-cancer families recruited for research purposes and in 6 of 49 probands referred to the Amsterdam Family Cancer Clinic for genetic counselling. In addition, a 3,835-bp Alu-mediated deletion encompassing exon 13 was detected in 4 of 170 research families, while an deletion of approximately 14 kb was detected in a single family [corrected]. Haplotype analyses indicated that each recurrent deletion had a single common ancestor.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Efeito Fundador , Mutação , Sequência de Bases , Southern Blotting , Neoplasias da Mama/epidemiologia , Desoxirribonuclease HindIII/genética , Desoxirribonuclease HindIII/metabolismo , Feminino , Haplótipos , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Países Baixos , Neoplasias Ovarianas/genética , Reação em Cadeia da Polimerase , Sequências Repetitivas de Ácido Nucleico , Deleção de SequênciaRESUMO
We have analyzed, by a combination of mutation and linkage analysis, the genetic basis of 22 breast cancer families in which at least 4 cases of either breast cancer diagnosed under the age of 60 or ovarian cancer had occurred. Chain-terminating mutations in BRCA1 were evidenced in 6 families, and posterior probabilities of > 0.90 of being linked to BRCA1 in 3. The breast versus ovarian cancer ratio in these 9 families was approximately 2:1. Among the remaining 13 families, significant linkage to markers flanking BRCA2 was established in the admixture test with a maximum multipoint lod score of 3.38, but there was no statistical evidence for genetic heterogeneity. The breast:ovarian cancer ratio in these families was 7:1, suggesting BRCA2 confers a much lower risk for ovarian cancer than does BRCA1. These results suggest that BRCA2 will explain a significant proportion of hereditary breast cancer in the Netherlands, and, together with BRCA1, account for the majority of all high-risk families.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Proteína BRCA2 , Neoplasias da Mama/epidemiologia , Feminino , Marcadores Genéticos , Humanos , Escore Lod , Modelos Genéticos , Mutação , Países Baixos/epidemiologia , Neoplasias Ovarianas/epidemiologia , Fatores de Risco , Análise de Sequência de DNARESUMO
We have identified 79 mutations in BRCA1 in a set of 643 Dutch and 23 Belgian hereditary breast and ovarian cancer families collected either for research or for clinical diagnostic purposes. Twenty-eight distinct mutations have been observed, 18 of them not previously reported and 12 of them occurring more than once. Most conspicuously, a 2804delAA mutation has been found 19 times and has never been reported outside the Netherlands. A common haplotype spanning > or = 375 kb could be identified for each of the nine examined recurrent mutations, indicating the presence of multiple BRCA1 founder mutations in the Dutch population. The 2804delAA mutation has been estimated to have originated approximately 32 generations ago. No specific breast or ovarian cancer phenotype could be assigned to any of the common mutations, and the ovarian cancer incidence among 18 families with the 2804delAA mutation was heterogeneous.