Assuntos
Carcinoma in Situ/patologia , Carcinoma in Situ/cirurgia , Gastrectomia/métodos , Gastroscopia/métodos , Síndrome de Muir-Torre/patologia , Síndrome de Muir-Torre/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Úlcera Gástrica/patologia , Úlcera Gástrica/cirurgia , Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma in Situ/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/patologia , Neoplasias Colorretais Hereditárias sem Polipose/cirurgia , Diagnóstico Precoce , Fator V/genética , Seguimentos , Triagem de Portadores Genéticos , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Síndrome de Muir-Torre/genética , Proteína 1 Homóloga a MutL , Mutação , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Proteínas Nucleares/genética , Protrombina/genética , Neoplasias Gástricas/genética , Úlcera Gástrica/genéticaRESUMO
Somatic epimutations in the MLH1 promoter mimic the phenotype of Lynch syndrome. To date, no somatic hypermethylation of the MLH1 promoter in the carrier of a pathogenic MLH1 germline mutation has been identified, prompting the recommendation that a germline mutation in MLH1 should only be sought in the absence of tumour tissue methylation. We aimed to determine whether methylation of the MLH1 promoter may coexist in carriers of a pathogenic germline mutation in MLH1. We examined the methylation status of the MLH1 promoter in 123 tumour tissue samples, demonstrating high microsatellite instability and loss of expression of a mismatch repair protein (60 cases with MLH1 germline mutation, 25 cases without mutation, 38 cases with MSH2 mutations), using combined bisulphite restriction analysis (COBRA) and SNaPshot analysis. Methylation of the MLH1 promoter was found in two patients with pathogenic germline mutations, one a carrier of a MLH1 mutation and the other a carrier of a MSH2 mutation. Our results demonstrate that methylation of the MLH1 promoter region does not exclude the presence of a germline mutation in a mismatch repair (MMR) gene. Hypermethylation of the MLH1 promoter may be present in most cases of sporadic colorectal cancers, but this does not exclude a diagnosis of Lynch syndrome.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias Colorretais Hereditárias sem Polipose/genética , Mutação em Linhagem Germinativa , Proteínas Nucleares/genética , Regiões Promotoras Genéticas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Metilação de DNA , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA/métodos , DNA de Neoplasias/genética , Humanos , Instabilidade de Microssatélites , Proteína 1 Homóloga a MutL , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismoRESUMO
The human MLC1( WKL1, KIAA0027) gene encodes a putative transmembrane protein expressed exclusively in brain. Recessive mutations within this gene cause megalencephalic leukoencephalopathy with subcortical cysts (MLC, MIM 604004, 605908). Furthermore, a missense mutation in this gene is suggestively linked with hereditary catatonic schizophrenia in a large pedigree. The murine gene Mlc1is composed of 12 exons spanning approximately 20 kb, and all exon-intron boundaries conform to the GT/AG consensus. The single copy transcript after splicing is approximately 2.8 kb in length, it contains 496 bp of 5' untranslated region (5'-UTR) and 1143 bp of 3'-UTR, and encodes a protein of 382 amino acids. Potential binding sites for transcription factors including CCAAT-boxes are present in the 5'-flanking region. Fluorescent in situ hybridization localizes the gene to mouse chromosome 15E-F, a region syntenic to human chromosome 22q13. The characterization of the genomic structure of the murine gene will facilitate studies of gene function and physiological properties of the encoded protein in transgenic mouse models.
