RESUMO
Recently BACH1, a novel putative DNA helicase mapping to chromosome 17q22, was reported to interact specifically with BRCA1, and was suggested to be a candidate gene for predisposition to breast and ovarian cancers. Here, we screened 214 breast and ovarian cancer patients from 151 Finnish families for germline BACH1 mutations by utilising conformation-sensitive gel electrophoresis (CSGE) and genomic sequencing analysis. Four sequence alterations were observed in the exon regions of BACH1, three of which have been previously reported and were classified as polymorphisms. In 1 patient, a novel heterozygous 3101C>T variant was observed resulting in a proline to leucine substitution at codon 1034 (Pro1034Leu). This amino acid change occurs in the BRCA1 binding domain of the BACH1 protein. Although the 3101C>T transition was also found in one of the 304 control individuals with an unknown cancer status, it still remains possible that this alteration could represent a rare disease-related allele in the population. Functional assays are needed to resolve the biological significance of this novel BACH1 missense variant. Altogether, the available data suggest that germline mutations in BACH1 are extremely rare.
Assuntos
Neoplasias da Mama/genética , Mutação de Sentido Incorreto/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Fatores de Transcrição de Zíper de Leucina Básica , DNA de Neoplasias/análise , Eletroforese em Gel de Poliacrilamida , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Finlândia , Testes Genéticos , Heterozigoto , Humanos , LinhagemAssuntos
Neoplasias da Mama/genética , Testes Genéticos , Mutação em Linhagem Germinativa/genética , Proteínas Serina-Treonina Quinases/genética , Adulto , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA , Éxons/genética , Feminino , Finlândia , Predisposição Genética para Doença/genética , Variação Genética/genética , Humanos , Masculino , Linhagem , Polimorfismo Genético/genética , Proteínas Supressoras de TumorRESUMO
In the Finnish population, identified mutations in BRCA1 and BRCA2 account for a less than expected proportion of hereditary breast and ovarian cancer. All previous studies performed in our country have concentrated on finding germ-line mutations in the coding and splice-site regions of these two genes. Therefore, we wanted to use a different methodological approach and search for large genomic rearrangements, to exclude the possibility of biased BRCA1 and BRCA2 mutation spectra due to known limitations of the previously used PCR-based detection methods. Our results support earlier notions that other genes than BRCA1 and BRCA2 will explain a majority of the still unexplained cases of hereditary susceptibility to breast and ovarian cancer.
Assuntos
Proteína BRCA1/genética , Neoplasias da Mama/genética , Testes Genéticos , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Deleção de Sequência , Fatores de Transcrição/genética , Proteína BRCA2 , Southern Blotting , Neoplasias da Mama/epidemiologia , Família , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Humanos , Neoplasias Ovarianas/epidemiologiaRESUMO
Recently CHK2 was functionally linked to the p53 pathway, and mutations in these two genes seem to result in a similar Li-Fraumeni syndrome (LFS) or Li-Fraumeni-like syndrome (LFL) multi-cancer phenotype frequently including breast cancer. As CHK2 has been found to bind and regulate BRCA1, the product of one of the 2 known major susceptibility genes to hereditary breast cancer, it also more directly makes CHK2 a suitable candidate gene for hereditary predisposition to breast cancer. Here we have screened 79 Finnish hereditary breast cancer families for germline CHK2 alterations. Twenty-one of these families also fulfilled the criteria for LFL or LFS. All families had previously been found negative for germline BRCA1, BRCA2 and TP53 mutations, together explaining about 23% of hereditary predisposition to breast cancer in our country. Only one missense-type mutation, Ile(157)-->Thr(157), was detected. The high Ile(157)--> Thr(157)mutation frequency (6.5%) observed in healthy controls and the lack of other mutations suggest that CHK2 does not contribute significantly to the hereditary breast cancer or LFL-associated breast cancer risk, at least not in the Finnish population. For Ile(157)--> Thr(157)our result deviates from what has been reported previously.
Assuntos
Neoplasias da Mama/genética , Mutação em Linhagem Germinativa , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases , Quinase do Ponto de Checagem 2 , Estudos de Coortes , Feminino , Humanos , Masculino , LinhagemRESUMO
We have screened for germline TP53 mutations in Finnish BRCA1 and BRCA2 mutation-negative families. This study represents the largest survey of the entire protein-encoding portion of TP53, and indicates that mutations are only found at conserved domains in breast cancer families also meeting the criteria for Li-Fraumeni/Li-Fraumeni-like syndrome, explaining only a very small additional fraction of the hereditary breast cancer cases.