RESUMO
Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome predisposing to tumors of the parathyroid, endocrine pancreas, anterior pituitary, adrenal glands, and diffuse neuroendocrine tissues. The MEN1 gene has been assigned, by linkage analysis and loss of heterozygosity, to chromosome 11q13 and recently has been identified by positional cloning. In this study, a total of 84 families and/or isolated patients with either MEN1 or MEN1-related inherited endocrine tumors were screened for MEN1 germ-line mutations, by heteroduplex and sequence analysis of the MEN1 gene-coding region and untranslated exon 1. Germ-line MEN1 alterations were identified in 47/54 (87%) MEN1 families, in 9/11 (82%) isolated MEN1 patients, and in only 6/19 (31.5%) atypical MEN1-related inherited cases. We characterized 52 distinct mutations in a total of 62 MEN1 germ-line alterations. Thirty-five of the 52 mutations were frameshifts and nonsense mutations predicted to encode for a truncated MEN1 protein. We identified eight missense mutations and five in-frame deletions over the entire coding sequence. Six mutations were observed more than once in familial MEN1. Haplotype analysis in families with identical mutations indicate that these occurrences reflected mainly independent mutational events. No MEN1 germ-line mutations were found in 7/54 (13%) MEN1 families, in 2/11 (18%) isolated MEN1 cases, in 13/19 (68. 5%) MEN1-related cases, and in a kindred with familial isolated hyperparathyroidism. Two hundred twenty gene carriers (167 affected and 53 unaffected) were identified. No evidence of genotype-phenotype correlation was found. Age-related penetrance was estimated to be >95% at age >30 years. Our results add to the diversity of MEN1 germ-line mutations and provide new tools in genetic screening of MEN1 and clinically related cases.
Assuntos
Mutação em Linhagem Germinativa , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla/genética , Mutação , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas , Substituição de Aminoácidos , Éxons , Feminino , Triagem de Portadores Genéticos , Humanos , Íntrons , Masculino , Neoplasia Endócrina Múltipla/classificação , Neoplasia Endócrina Múltipla Tipo 1/classificação , Mutação de Sentido Incorreto , Linhagem , Mutação Puntual , Deleção de SequênciaAssuntos
Polipose Adenomatosa do Colo/genética , Mutação em Linhagem Germinativa , Monoéster Fosfórico Hidrolases , Proteínas Tirosina Fosfatases/genética , Proteínas Supressoras de Tumor , Polipose Adenomatosa do Colo/enzimologia , Idoso , Variação Genética , Humanos , Masculino , PTEN Fosfo-HidrolaseAssuntos
Neoplasias da Mama/genética , Mutação , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/genética , Fatores de Transcrição/genética , Adulto , Proteína BRCA2 , Neoplasias da Mama/epidemiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/epidemiologiaRESUMO
Although more than 100 different BRCA1 germ-line mutations have already been identified in breast and/or ovarian cancer families, we report for the first time a deleterious genomic rearrangement in BRCA1. A 1-kb deletion comprising exon 17 was found in a large breast and ovarian cancer family, leading to a frameshift in the mutant mRNA due to the absence of exon 17. This deletion is probably the result of a recombination between two closely related Alu sequences. It was not detected by conventional PCR-based methods involving the genomic screening of the 22 coding exons or reverse transcription-PCR because the transcript without exon 17 is unstable in lymphoblastoid cell lines. Therefore, rearrangements in the BRCA1 gene should be sought in breast/ovarian cancer families in which no mutations have been found by PCR-based methods in the coding region or in the splice sites.
