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1.
BMC Med Genet ; 7: 5, 2006 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-16426447

RESUMO

BACKGROUND: Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant syndrome predisposing to the early development of various cancers including those of colon, rectum, endometrium, ovarium, small bowel, stomach and urinary tract. HNPCC is caused by germline mutations in the DNA mismatch repair genes, mostly hMSH2 or hMLH1. In this study, we report the analysis for genetic counseling of three first-degree relatives (the mother and two sisters) of a male who died of colorectal adenocarcinoma at the age of 23. The family fulfilled strict Amsterdam-I criteria (AC-I) with the presence of extracolonic tumors in the extended pedigree. We overcame the difficulty of having a proband post-mortem non-tumor tissue sample for MSI testing by studying the alleles carried by his progenitors. METHODS: Tumor MSI testing is described as initial screening in both primary and metastasis tumor tissue blocks, using the reference panel of 5 microsatellite markers standardized by the National Cancer Institute (NCI) for the screening of HNPCC (BAT-25, BAT-26, D2S123, D5S346 and D17S250). Subsequent mutation analysis of the hMLH1 and hMSH2 genes was performed. RESULTS: Three of five microsatellite markers (BAT-25, BAT-26 and D5S346) presented different alleles in the proband's tumor as compared to those inherited from his parents. The tumor was classified as high frequency microsatellite instability (MSI-H). We identified in the HNPCC family a novel germline missense (c.1864C>A) mutation in exon 12 of hMSH2 gene, leading to a proline 622 to threonine (p.Pro622Thr) amino acid substitution. CONCLUSION: This approach allowed us to establish the tumor MSI status using the NCI recommended panel in the absence of proband's non-tumor tissue and before sequencing the obligate carrier. According to the Human Gene Mutation Database (HGMD) and the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) Database this is the first report of this mutation.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Análise Mutacional de DNA/métodos , Mutação em Linhagem Germinativa , Repetições de Microssatélites , Proteína 2 Homóloga a MutS/genética , Adulto , Sequência de Aminoácidos , Análise Mutacional de DNA/normas , Feminino , Testes Genéticos , Instabilidade Genômica , Humanos , Masculino , Dados de Sequência Molecular , National Institutes of Health (U.S.) , Linhagem , Proteínas/genética , Padrões de Referência , Alinhamento de Sequência , Estados Unidos
2.
Hum Mutat ; 23(5): 523-4, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15108288

RESUMO

We examined the adenomatous polyposis coli (APC) gene for disease-causing mutations in 51 unrelated Argentinean probands affected by familial adenomatous polyposis (FAP). Using a combination of the protein truncation test, the single strand conformation polymorphism technique, DNA sequencing and quantitative PCR analysis, we identified the specific mutation in 39 (average age: 28.4 years) of the 51 probands (detection rate: 76.47%); 13 are novel germline mutations and one is a novel sequence variant. There were 27 small deletions, four small duplications, five nonsense mutations in exon 15, three nonsense mutations in exons 6, 11, and 12, and one sequence variant in exon 3 identified in a patient bearing a truncating mutation in exon 15. The most common mutation (found in 10 cases) was at codon 1309. All patients negative for APC mutations were also negative for the MutY homolog (MYH) gene mutation, as expected because of fully penetrant FAP cases. This study enlarges the spectrum of APC gene mutations, and reinforces the concept of mutation heterogeneity. It also sheds light on correlations between the site of APC germline mutations and the clinical manifestations of FAP. Our data indicate that the genotype/phenotype correlations in Argentinean patients are similar to those observed in other populations.


Assuntos
Polipose Adenomatosa do Colo/genética , Genes APC , Mutação , Polipose Adenomatosa do Colo/diagnóstico , Adolescente , Adulto , Argentina , Pré-Escolar , Análise Mutacional de DNA , Genótipo , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade
3.
Medicina (B Aires) ; 63(1): 41-5, 2003.
Artigo em Espanhol | MEDLINE | ID: mdl-12673960

RESUMO

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.


Assuntos
Carcinoma Medular/genética , Proteínas de Drosophila , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proteínas Proto-Oncogênicas/genética , Proto-Oncogenes , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Calcitonina/análise , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Proteínas Proto-Oncogênicas c-ret
4.
Medicina (B.Aires) ; Medicina (B.Aires);63(1): 41-45, 2003. tab
Artigo em Espanhol | LILACS | ID: lil-334545

RESUMO

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Carcinoma Medular , Neoplasia Endócrina Múltipla Tipo 2a , Proteínas Proto-Oncogênicas , Proto-Oncogenes , Neoplasias da Glândula Tireoide , Calcitonina , Códon , Mutação , Fenótipo , Tireoidectomia
5.
Medicina (B.Aires) ; 63(1): 41-5, 2003.
Artigo em Espanhol | BINACIS | ID: bin-39013

RESUMO

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5


is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17


) or 2B (3


). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85


) presented the mutation. Seven (28


) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed.

6.
Medicina (B.Aires) ; 63(1): 41-45, 2003. tab
Artigo em Espanhol | BINACIS | ID: bin-6608

RESUMO

Twenty five percent of the medullary thyroid carcinoma (MTC) is hereditary and 5% is familiar (FMTC), or considered as multiple endocrine neoplasia (MEN) type 2A (17%) or 2B (3%). These diseases are the result of the autosomic dominant inheritance of a mutation in the RET protooncogene, in one out of 12 different known codons. We analyzed 7 families (2 MEN 2A and 5 FMTC). Six mutations were detected in the most frequent codon, 634 (2 MEN 2A y 4 FMTC) and one family with FMTC presented a novel mutation: a transition T > C at codon 630, resulting a C630A change. Among 57 individuals studied, 25 (43.85%) presented the mutation. Seven (28%) were asymptomatic carriers, including 5 children aged 11 +/- 3.2 years. The children underwent total thyroidectomy. The histopathologic examination showed C cells hyperplasia and microcarcinoma focus in both lobes, even in the presence of normal, basal or pentagastrine stimulated, calcitonine levels. In conclusion, we describe a germine novel mutation in the RET protooncogene: C630A; and the corresponding findings of C-cell disease in gene mutated carriers that emphasize the importance of prophylactic thyroidectomy as soon as the molecular diagnosis is confirmed (AU)


Assuntos
Humanos , Masculino , Feminino , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , RESEARCH SUPPORT, NON-U.S. GOVT , Carcinoma Medular/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Proto-Oncogenes , Neoplasias da Glândula Tireoide/genética , Proteínas Proto-Oncogênicas/genética , Mutação , Códon , Tireoidectomia , Calcitonina/análogos & derivados , Fenótipo
7.
Eur J Hum Genet ; 10(6): 395-7, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12080393

RESUMO

Sequencing an amplification product of the terminal segment of BRCA2 exon 11 showed apparent homozygosity for the 6174delT mutation in two healthy sisters. Subsequent sequencing of an alternate overlapping amplicon revealed the presence of the 5972C >T polymorphism, which is within the standard upstream amplification primer. This mismatch was responsible for the failure to amplify the normal (5972T) allele in both sisters who were heterozygous for the 6174delT mutation. Though the unexpected finding of apparent homozygosity for the 6174delT mutation prompted re-evaluation of the assay, the potential for false negative results due to masking of a mutation-bearing allele by such a circumstance should be a cautionary note for the testing and also in the interpretation of the results published under such assay conditions.


Assuntos
Genes BRCA2 , Técnicas de Amplificação de Ácido Nucleico , Polimorfismo de Nucleotídeo Único , Deleção de Sequência , Primers do DNA , Reações Falso-Positivas , Feminino , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
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