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The most commun form of hereditary colon cancer called Heredity non-polyposis colon cancer (HNPCC) or Lynch syndrome (OMIM 120436) is a syndrome of deficient DNA mismatch repair (MMR). It represents 3 to 5% of colorectal cancer. Six human MMR genes have been identified to cause susceptibility to this syndrome. These genes are hML1 (3q21.3), hMSH2 (2p22-21), hPMS1 (2p31-33), hPMS2 (7p22), hMSH6 (2p16) and hMSH3 (5q11-12). Up to now more than 300 different predisposing mutations are known, mainly affecting the MMR genes hMLH1 (≈50%), hMSH2 (≈40%) and hMSH6 (≈10%) (http://nfdht.nl/database.htm). Genetically predisposed individuals carry a defective copy of an MMR gene in every cell. Somatic inactivation of the remaining wild-type copy in a target tissue, typically colon, gives rise to a profound repair defect, progressive accumulation of mutations and finally cancer. Instability at short tandem repeat sequences, microsatellites (CA – repeat ou poly-adenine), is a typical manifestation of MMR deficient and apart from HNPCC tumours, occurs ≈ 13% of sporadic colon and other tumors (Kinzler and Vogelstein, 1996).
The aim of this study is to assess the role of the hMLH1 and hMSH2 gene in the colorectal cancers. We analysed and studied the tumors of 500 patients, tumours analysed at the Centre of human genetics of UCL-Cliniques Universitaires St-Luc (Spetembre 1998 to January 2001). Out of this group 54 patients were selected on the family history, Bethesda, Amsterdam I or Amsterdam II criteria, microsatellite instability (MSI+) and immunohistochemical tests (for the hMLH1 and hMSH2 protein).
The loss of hMLH1 and hMSH2 protein at tumour level is shown for orientate the search for mutations to the hMLH1 or hMSH2 gene and was carried by the group of anatomopahtology of St-Luc. We performed pathogenic germline mutations by Denaturin Gradient Gel Electrophoresis (DGGE).
In total, 20 germline mutations (16 in hMLH1 and 4 in hMSH2) in 19 patients confirmed the diagnosis of Lynch syndrome. However only 4 mutations were discovered in 21 patients analysed in hMSH2 gene. These data incited to begin a search of deletion of complete exons. This search with the quantitative PCR amplification and then the interpretation with the 310 Applied Biosystems and Gene Scan software showed only one deletion.
The last step of this work was to compare the positive mutations group with the negative mutations group concerning adenoma location, age of the diagnostic, presence of extracolon cancer and family history. We also compared the mutation type (missense or mutation affecting the protein length) with the family history. The conclusion of this part of the work shows there are not predictive factors which could lead to positive mutation in a suspected family. However when Amsterdam I criteria is present in a family there is probably one mutation affecting the protein length (4 mutations in 6 Amsterdam I family) La plus importante des formes héréditaires de cancer du côlon est le Cancer du Côlon Non-Polyposique Héréditaire (HNPCC) ou syndrome de Lynch (OMIM 120436). Il est un syndrome de déficience du Système de Réparation es Mésappariements de l’ADN (SRN). Il représente 3 à 5% des cancers colorectaux. Six gènes humains ont été identifiés dans le SRM. Ces gènes sont hMLH1 (3q21.3), hMSH2 (2p22-21, hPMS1 (2p31-33, hPMS2 (7p22), hMSH6 (2p16) et hMSH3(5q11-12). A ce jour, plus de 300 mutations différentes sont connues pour affecter les gènes du SRM, réparties en hMLH1 (≈50%), hMSH2 (≈40%) et hMSH6 (≈10%) (http://nfdht.nl/database.htm) . Généralement une prédisposition individuelle est due à un défaut dans une copie d’un gène du SRM de chaque cellule. Une inactivation somatique de la copie normale restante dans un tissu spécifique comme le côlon donne un défaut du système de réparation. Ceci engendre une accumulation de mutations et finalement le cancer. L’instabilité de courtes séquences de répétition comme les microsatellites (motif CA ou poly-adénine) est un signe d’une déficience du SRM qui apparaît dans les tumeurs du syndrome HNPCC, excepté dans 13% qui sont des cas sporadiques (Kinzler and Vogelstein, 1996).
le but de cette étude est d’évaluer le rôle des gènes hMLH1 et hMSH2 dans le cancer colorectal. Les tumeurs de 500 patients ont été analysées et étudiées au Centre de Génétique Humaine de l’UCL-Cliniques Universitaires Saint-Luc (de septembre 1998 à janvier 2001). A partir de ce groupe, 54 patients ont été sélectionnés selon l’histoire familiale (les critères de Bethesda, Amsterdam I ou Amsterdam AA), l’instabilité de microsatellites (statuts MSI+) et l’analyse immunohistochimique (pour les protéines hMLH1 et hMSH2).
La détection de la perte des protéines hMLH1 et hMSH2 au niveau tumoral a été réalisée par le service d’anatomopathologie des Cliniques Universitaires Saint-Luc. Ces résultats orientent la recherche des mutations germinales pathologiques vers les gènes hMLH1 et hMSH2, recherche effectuée par l’Electrophorèse en Gradient d’Agents Dénaturants (DGGE).
Au total, 20 mutations germinales (16 dans hMLH2 et 4 dans hMSH2) dont 13 nouvelles et non rapportées à ce jour, confirment le diagnostic de syndrome de Lynch chez 19 patients. Des ces mutations, la Q689R siège dans un domaine fonctionnel du gène hMLH1 (liaison avec la protéine hPMS2). Elle est responsable de la substitution d’une glutamine en arginine au codon 689. Cette mutation ne coségrège pas avec le syndrome de Lynch dans la famille, raison pour laquelle elle n’est pas considérée comme mutation pathogénique. L’analyse moléculaire du gène hMSH2 a été compétée chez 21 patients par un dosage génique du signal émis lors de l’amplification PCR par un fluorochrome incorporé dans l’amorce sens (Applied Biosystems 310 – logiciel Gene Scan) afin de détecter de larges remaniements. Une délétion limitée aux exons 2 et 3 a été identifiée par cette approche augmentant le nombre de mutations découvertes à 21.
La dernière étape de ce travail a comparé les caractéristiques cliniques et familiales du groupe de patients avec mutation positive au groupe de patients sans mutation identifiée : la localisation de l’adénocarcinome, l’âge au moment du diagnostic et la présence de cancers extracoliques. Nous avons également corrélé la nature de la mutation (faux-sens / affectant la longueur de la protéine) à l’histoire familiale afin d’évaluer la sévérité clinique de la mutation. L’étude des corrélations génotypes-phénotypes confirme l’importance des critères cliniques élaborés à Amsterdam (Vasen et al., 1991). Ces critères prédisent un syndrome de Lynch avec confirmation moléculaire dans 60% des cas. De plus, dans la majorité des familles Amsterdam I avec mutation identifiée (4/6), l’anomalie génétique module la longueur de la protéine hMLH1. De façon inattendue, plus d’un tiers des familles caractérisées par un risque moindre de cancers héréditaires du côlon (Bethesda, 1 CCR dans la famille) sont réellement des syndrome de Lynch avec identification de mutations principalement dans hMSH2. Dans les familles atteintes du syndrome de Lynch avec confirmation moléculaire des tumeurs extracolique : tumeurs d’origines gastrique, cutanée et gynécologique sont également dénombrées. Ces différentes tumeurs appartiendraient donc au spectre HNPCC en Belgique

Colonic Neoplasms --- Neoplastic syndromes, hereditary --- Genetic Predisposition to Disease

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Cancer --- Neoplasms --- Ethics, Medical --- Neoplastic Syndromes, Hereditary --- Environmental aspects --- Congresses. --- Genetic aspects --- genetics --- congresses. --- Congresses

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Neurocutaneous diseases are a wide group of conditions that affect the nervous system but appear as lesions of the skin. Some of the more common entities have variable forms of expression that can confuse the diagnosis; for the rare conditions it is difficult to find descriptions in the literature. Recent insights into their cellular, biochemical and molecular genetic bases have shown the essential need for a new nosology and updated genotype-phenotype correlations. The book provides an authoritative source of knowledge about these difficult problems and bridges the gap between clinical recognition and the new molecular medicine. The editors, distinguished clinicians and geneticists, assembled an internationally renowned group of collaborators, many of them the experts who first described a particular disorder or established its present accepted definition. They have written a practical, comprehensive guide to the recognition, investigation and management of more than 60 recognised phakomatoses.

Medicine & Public Health. --- Neurology. --- Pediatrics. --- Human Genetics. --- Neurosurgery. --- Orthopedics. --- Dermatology. --- Medicine. --- Human genetics. --- Médecine --- Génétique humaine --- Dermatologie --- Neurologie --- Orthopédie --- Pédiatrie --- Neurocutaneous disorders. --- Skin -- Diseases. --- Neurocutaneous Syndromes --- Hamartoma --- Neoplastic Syndromes, Hereditary --- Hemangioma --- Neoplasms, Vascular Tissue --- Ectodermal Dysplasia --- Neoplasms --- Nervous System Diseases --- Genetic Diseases, Inborn --- Diseases --- Skin Abnormalities --- Abnormalities, Multiple --- Skin Diseases, Genetic --- Congenital, Hereditary, and Neonatal Diseases and Abnormalities --- Neoplasms by Histologic Type --- Congenital Abnormalities --- Skin Diseases --- Skin and Connective Tissue Diseases --- Neurology --- Dermatology --- Medicine --- Health & Biological Sciences --- Phakomatoses. --- Dermatoneurosis --- Neurodermatitis --- Phacomatoses --- Genetic disorders --- Multiple tumors --- Neurocutaneous disorders --- Nervous system --- Skin --- Orthopaedics --- Orthopedia --- Surgery --- Nerves --- Neurosurgery --- Paediatrics --- Pediatric medicine --- Children --- Genetics --- Heredity, Human --- Human biology --- Physical anthropology --- Neuropsychiatry --- Health and hygiene --- Neurology .

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In this book we have taken a comprehensive look at the subject of familial and hereditary gastric tumors. In particular, the aim of this novel editorial work is to propose the correct management of hereditary diffuse gastric cancer patients, focusing in particular on E-cadherin germline mutations, clinical criteria definition, genetic screening and molecular mechanisms, pathology and microscopic features, surgical treatment and clinical approach for asymptomatic mutation carriers. We also describe other inherited predispositions involving gastric carcinoma.

Cancer -- Genetic aspects. --- Neoplasms -- genetics. --- Stomach --- Disease Susceptibility --- Gastrointestinal Neoplasms --- Neoplasms --- Biology --- Digestive System Neoplasms --- Biological Science Disciplines --- Diseases --- Disease Attributes --- Neoplasms by Site --- Pathologic Processes --- Natural Science Disciplines --- Pathological Conditions, Signs and Symptoms --- Disciplines and Occupations --- Genetic Predisposition to Disease --- Neoplastic Syndromes, Hereditary --- Stomach Neoplasms --- Genetics --- Medicine --- Health & Biological Sciences --- Oncology --- Cancer --- Genetic aspects --- Cancer. --- Diseases. --- Cancers --- Carcinoma --- Malignancy (Cancer) --- Malignant tumors --- Gastric diseases --- Medicine. --- Cancer research. --- Human genetics. --- Gastroenterology. --- Biomedicine. --- Cancer Research. --- Biomedicine general. --- Human Genetics. --- Tumors --- Oncology. --- Clinical sciences --- Medical profession --- Human biology --- Life sciences --- Medical sciences --- Pathology --- Physicians --- Heredity, Human --- Physical anthropology --- Internal medicine --- Digestive organs --- Gastroenterology . --- Biomedicine, general. --- Health Workforce --- Cancer research

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The initial identification of the Adenomatous polyposis coli (Apc) gene as the site of mutations in familial adenomatous polyposis (FA P) was described in 1992. A causal relationship between Apc mutations and intestinal tract tumours was confirmed three years later with the establishment of the Min mouse model. These mice are heterozygous for Apc and develop numerous intestinal tumours that mimic FA P. Subsequently, Apc has emerged as the most commonly mutated gene in colorectal cancer with reports varying between 50-80 per cent of sporadic tumours carrying such mutations. The search for how m

Adenomatous Polyposis Coli Protein. --- Adenomatous Polyposis Coli. --- Colon (Anatomy) -- Cancer. --- Colorectal Neoplasms -- Metabolism. --- Genes, APC. --- Tumor suppressor proteins. --- Colon (Anatomy) --- Tumor suppressor proteins --- Adenomatous Polyposis Coli --- Colorectal Neoplasms --- Genes, APC --- Metabolism --- Adenomatous Polyposis Coli Protein --- Intestinal Polyposis --- Intestinal Neoplasms --- Colonic Neoplasms --- Neoplastic Syndromes, Hereditary --- Colonic Diseases --- Metabolic Phenomena --- Cytoskeletal Proteins --- Genes, Tumor Suppressor --- Tumor Suppressor Proteins --- Rectal Diseases --- Adenomatous Polyps --- Proteins --- Neoplasm Proteins --- Intestinal Diseases --- Neoplasms --- Genes, Neoplasm --- Phenomena and Processes --- Gastrointestinal Neoplasms --- Genes, Recessive --- Adenoma --- Genetic Diseases, Inborn --- Gastrointestinal Diseases --- Digestive System Neoplasms --- Genes --- Diseases --- Neoplasms, Glandular and Epithelial --- Congenital, Hereditary, and Neonatal Diseases and Abnormalities --- Amino Acids, Peptides, and Proteins --- Chemicals and Drugs --- Digestive System Diseases --- Genome Components --- Neoplasms by Site --- Neoplasms by Histologic Type --- Genome --- Genetic Structures --- Genetic Phenomena --- Oncology --- Medicine --- Health & Biological Sciences --- Cancer --- Cancer. --- Antioncoproteins --- Growth suppressor proteins --- Metastasis suppressor proteins --- Colon cancer --- Colorectal cancer --- Medicine. --- Biomedicine. --- Biomedicine general. --- Clinical sciences --- Medical profession --- Human biology --- Life sciences --- Medical sciences --- Pathology --- Physicians --- Antioncogenes --- Health Workforce --- Biomedicine, general.