RESUMO
Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal dominant condition defined by the development of characteristic polyps throughout the gastrointestinal tract and mucocutaneous pigmentation. The majority of patients that meet the clinical diagnostic criteria have a causative mutation in the STK11 gene, which is located at 19p13.3. The cancer risks in this condition are substantial, particularly for breast and gastrointestinal cancer, although ascertainment and publication bias may have led to overestimates in some publications. Current surveillance protocols are controversial and not evidence-based, due to the relative rarity of the condition. Initially, endoscopies are more likely to be done to detect polyps that may be a risk for future intussusception or obstruction rather than cancers, but surveillance for the various cancers for which these patients are susceptible is an important part of their later management. This review assesses the current literature on the clinical features and management of the condition, genotype-phenotype studies, and suggested guidelines for surveillance and management of individuals with PJS. The proposed guidelines contained in this article have been produced as a consensus statement on behalf of a group of European experts who met in Mallorca in 2007 and who have produced guidelines on the clinical management of Lynch syndrome and familial adenomatous polyposis.
Assuntos
Síndrome de Peutz-Jeghers/diagnóstico , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Criança , Pré-Escolar , Endoscopia Gastrointestinal , Medicina Baseada em Evidências/métodos , Feminino , Neoplasias Gastrointestinais/diagnóstico , Neoplasias dos Genitais Femininos/diagnóstico , Genótipo , Humanos , Assistência de Longa Duração/métodos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Fenótipo , Vigilância da População/métodos , Adulto JovemRESUMO
BACKGROUND: Familial adenomatous polyposis (FAP) is a well-described inherited syndrome, which is responsible for <1% of all colorectal cancer (CRC) cases. The syndrome is characterised by the development of hundreds to thousands of adenomas in the colorectum. Almost all patients will develop CRC if they are not identified and treated at an early stage. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the APC gene. Recently, a second gene has been identified that also gives rise to colonic adenomatous polyposis, although the phenotype is less severe than typical FAP. The gene is the MUTYH gene and the inheritance is autosomal recessive. In April 2006 and February 2007, a workshop was organised in Mallorca by European experts on hereditary gastrointestinal cancer aiming to establish guidelines for the clinical management of FAP and to initiate collaborative studies. Thirty-one experts from nine European countries participated in these workshops. Prior to the meeting, various participants examined the most important management issues according to the latest publications. A systematic literature search using Pubmed and reference lists of retrieved articles, and manual searches of relevant articles, was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described herein may be helpful in the appropriate management of FAP families. In order to improve the care of these families further, prospective controlled studies should be undertaken.
Assuntos
Polipose Adenomatosa do Colo/terapia , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Idade de Início , Anti-Inflamatórios não Esteroides/uso terapêutico , Neoplasias Duodenais/diagnóstico , Neoplasias Duodenais/terapia , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/terapia , Genes APC , Predisposição Genética para Doença , Testes Genéticos/métodos , Humanos , Masculino , Fatores de RiscoRESUMO
Lynch syndrome (hereditary non-polyposis colorectal cancer) is characterised by the development of colorectal cancer, endometrial cancer and various other cancers, and is caused by a mutation in one of the mismatch repair genes: MLH1, MSH2, MSH6 or PMS2. The discovery of these genes, 15 years ago, has led to the identification of large numbers of affected families. In April 2006, a workshop was organised by a group of European experts in hereditary gastrointestinal cancer (the Mallorca-group), aiming to establish guidelines for the clinical management of Lynch syndrome. 21 experts from nine European countries participated in this workshop. Prior to the meeting, various participants prepared the key management issues of debate according to the latest publications. A systematic literature search using Pubmed and the Cochrane Database of Systematic Reviews reference lists of retrieved articles and manual searches of relevant articles was performed. During the workshop, all recommendations were discussed in detail. Because most of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, many of them were based on expert opinion. The guidelines described in this manuscript may be helpful for the appropriate management of families with Lynch syndrome. Prospective controlled studies should be undertaken to improve further the care of these families.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/terapia , Guias de Prática Clínica como Assunto , Colo/patologia , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias do Endométrio/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Testes Genéticos , HumanosAssuntos
Proteínas de Ligação a DNA/genética , Neoplasias do Endométrio/genética , Mutação em Linhagem Germinativa , Heterozigoto , Neoplasias Colorretais Hereditárias sem Polipose/genética , Saúde da Família , Feminino , Humanos , Neoplasias Ovarianas/genética , Neoplasias da Bexiga Urinária/genéticaRESUMO
PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by the clustering of colorectal cancer, endometrial cancer, and various other cancers. The disease is caused by mutations in DNA-mismatch-repair (MMR) genes, most frequently in MLH1, MSH2, and MSH6. The aims of the present study were to compare the risk of developing colorectal, endometrial, and other cancers between families with the various MMR-gene mutations. PATIENTS AND METHODS: Clinical and pathologic data were collected from 138 families with HNPCC. Mutation analyses were performed for all families. Survival analysis was used to calculate the cumulative risk of developing cancer in the various subsets of relatives. RESULTS: Mutations were identified in 79 families: 34 in MLH1, 40 in MSH2, and five in MSH6. The lifetime risk of developing cancer at any site was significantly higher for MSH2 mutation carriers than for MLH1 mutation carriers (P < .01). The risk of developing colorectal or endometrial cancer was higher in MSH2 mutation carriers than in MLH1 mutation carriers, but the difference was not significant (P = .13 and P = .057, respectively). MSH2 mutation carriers were found to have a significantly higher risk of developing cancer of the urinary tract (P < .05). The risk of developing cancer of the ovaries, stomach, and brain was also higher in the MSH2 mutation carriers than in the MLH1 mutation carriers, but the difference was not statistically significant. CONCLUSION: Pending large prospective studies, the extension of the current surveillance program in MSH2 mutation carriers with the inclusion of the urinary tract should be considered.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Proteínas de Ligação a DNA , Mutação , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Pareamento Incorreto de Bases/genética , Proteínas de Transporte , Criança , Pré-Escolar , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo do DNA/genética , Feminino , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Países Baixos/epidemiologia , Proteínas Nucleares , Sistema de Registros , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND AND AIMS: Hereditary non-polyposis colorectal cancer (HNPCC) may be caused by mutations in the mismatch repair (MMR) genes MLH1, MSH2 or MSH6. Family history (Amsterdam criteria) has traditionally been used to select patients for mutation testing. It has been demonstrated that germline mutations in the MMR genes are associated with lack of the corresponding gene product as assessed with immunohistochemistry (IHC) in tumour specimens. The aim of the study was to assess the value of the Amsterdam criteria II and IHC in predicting germline mutations. METHODS: Fifty-six families that were previously tested for MLH1, MSH2 and MSH6 mutations were selected for this study. All pedigrees were extended and verified and the families were scored according to the original (I) and the revised Amsterdam criteria (II). The probabilities for MLH1 and MSH2 mutations were calculated by logistic regression. In addition, all available tumour material from indexed family members was examined by IHC for the presence of the three gene products. RESULTS: Three out of seven (39%) families where the mutation could be identified complied with the Amsterdam criteria I, while all seven (100%) met the Amsterdam criteria II. All families carrying a MLH1 or MSH2 mutation had > 15% calculated probability of finding a mutation. Tumours from all seven mutation carriers lacked the immunohistochemical expression of the corresponding MMR gene. CONCLUSION: The results indicate that the Amsterdam criteria II in combination with immunohistochemistry of the mismatch repair proteins in tumours may be a cost-effective approach to select families for mutation analysis.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/metabolismo , Proteínas de Ligação a DNA/metabolismo , Testes Genéticos , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenoma/genética , Adenoma/metabolismo , Adulto , Pareamento Incorreto de Bases , Proteínas de Transporte , Reparo do DNA , DNA de Neoplasias , Feminino , Mutação em Linhagem Germinativa , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Proteína 2 Homóloga a MutS , Países Baixos , Proteínas Nucleares , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
To assess the impact of ATLS education on early trauma management, charts of patients with an ISS of 14 or greater were reviewed for a 1 year period before and after ATLS training of emergency room trauma care providers. There were 50 patients in the before ATLS group, with a mean age of 41.6 years and an ISS of 29.8, and 71 patients in the after ATLS group, with a mean age of 40.6 years and an ISS of 30.6. Of those parameters evaluated as measures of early assessment, only rectal examination was found to be performed significantly more frequently after ATLS training. The mortality rates of 26 percent before ATLS and 20 percent after ATLS were not significantly different. In evaluating assessment and management parameters in the patients who died, no airway management errors were found in the after ATLS group; however, there were more missed injuries in this group. We have concluded that ATLS instruction failed to produce a quantifiable improvement in patient assessment or outcome. Further studies directed at assessing the retention rate for ATLS education and determining the impact on clinical performance are needed.
Assuntos
Capacitação em Serviço , Cuidados para Prolongar a Vida , Traumatologia/educação , Ferimentos e Lesões/terapia , Adulto , Erros de Diagnóstico , Humanos , Avaliação de Processos e Resultados em Cuidados de Saúde , Estudos Retrospectivos , Ferimentos e Lesões/diagnóstico , Ferimentos e Lesões/mortalidadeRESUMO
Familial colorectal cancer (CRC) accounts for 10-15% of all CRCs. In about 5% of all cases, CRC is associated with a highly penetrant dominant inherited syndrome. The most common inherited form of non-polyposis CRC is the Lynch syndrome which is responsible for about 2-4% of all cases. Surveillance of individuals at high risk for CRC prevents the development of advanced CRC. About 1 million individuals in Western Europe are at risk for Lynch syndrome. We performed a survey to evaluate the strategies currently used to identify individuals at high risk for CRC in 14 Western European countries. Questionnaires were distributed amongst members of a European collaborative group of experts that aims to improve the prognosis of families with hereditary CRC. The survey showed that in all countries obtaining a family history followed by referral to clinical genetics centres of suspected cases was the main strategy to identify familial and hereditary CRC. In five out of seven countries with a (regional or national) CRC population screening program, attention was paid in the program to the detection of familial CRC. In only one country were special campaigns organized to increase the awareness of familial CRC among the general population. In almost all countries, the family history is assessed when a patient visits a general practitioner or hospital. However, the quality of family history taking was felt to be rather poor. Microsatellite instability testing (MSI) or immunohistochemical analysis (IHC) of CRC are usually recommended as tools to select high-risk patients for genetic testing and are performed in most countries in patients suspected of Lynch syndrome. In one country, IHC was recommended in all new cases of CRC. In most countries there are no specific programs on cancer genetics in the teaching curriculum for medical doctors. In conclusion, the outcome of this survey and the discussions within an European expert group may be used to improve the strategies to identify individuals at high risk of CRC. More attention should be given to increasing the awareness of the general population of hereditary CRC. Immunohistochemical analysis or MSI-analysis of all CRCs may be an effective tool for identifying all Lynch syndrome families. The cost-effectiveness of this approach should be further evaluated. All countries with a CRC population screening program should obtain a full family history as part of patient assessment.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Reparo de Erro de Pareamento de DNA , Europa (Continente)/epidemiologia , Aconselhamento Genético , Predisposição Genética para Doença , Testes Genéticos , Diretrizes para o Planejamento em Saúde , Humanos , Anamnese , Proteína 2 Homóloga a MutS/genética , Mutação , Linhagem , Fatores de RiscoRESUMO
About 13% of all colorectal cancer may be dominantly inherited. This amounts to about 300 new cases a year in Norway. Colorectal cancer can be cured by early diagnosis and treatment. Coloscopy with polypectomy may prevent infiltrating cancer. Affected families should be offered genetic evaluation, and family members subjected to regular colonoscopy. The genetic bases of five colorectal cancer syndromes, accounting for most cases of hereditary early onset colorectal cancer, have now been determined. These are familial adenomatous polyposis, colon-endometrial cancer (hereditary non-polyposis colon cancer), Cowden's syndrome, Peutz-Jegher's syndrome and juvenile polyposis. These account for at most 3% of all colorectal cancers. In this group, predictive genetic testing may be employed in families with known mutation. Demonstration of mutation carriers by predictive testing must be based on health service available to the persons at risk. With regard to prophylactic measures, experimental and epidemiological data suggest a preventive effect of aspirin and resistant starch. Empirical information on the effect of intervention is insufficient; multicentre studies are needed.
Assuntos
Neoplasias do Colo/genética , Predisposição Genética para Doença , Neoplasias Retais/genética , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/prevenção & controle , Neoplasias do Colo/prevenção & controle , Humanos , Mutação , Noruega , Neoplasias Retais/prevenção & controle , Fatores de RiscoRESUMO
Instability of microsatellite repeat sequences has been observed in colorectal carcinomas and in extracolonic malignancies, predominantly endometrial tumours, occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability (MSI) as a feature of human DNA mismatch repair (MMR)-driven tumourigenesis of the uterine mucosa has been studied primarily in sporadic tumours showing predominantly somatic hypermethylation of MLH1. The present study shows that all endometrial carcinomas (n=12) from carriers of MLH1 and MSH2 germline mutations demonstrate an MSI-high phenotype involving all types of repeat markers, while in endometrial carcinomas from MSH6 mutation carriers, only 36% (4 out of 11) demonstrate an MSI-high phenotype. Interestingly, an MSI-high phenotype was found in endometrial hyperplasias from MSH2 mutation carriers, in contrast to hyperplasias from MLH1 mutation carriers, which exhibited an MSI-stable phenotype. Instability of only mononucleotide repeat markers was found in both endometrial carcinomas and hyperplasias from MSH6 mutation carriers. In 29 out of 31 (94%) endometrial tumour foci, combined MSI and immunohistochemical analysis of MLH1, MSH2, and MSH6 could predict the identified germline mutation. The observation of MSI in endometrial hyperplasia and of altered protein staining for the MMR genes supports the idea that inactivation of MMR genes is an early event in endometrial tumourigenesis. A correlation was found between the variation in the extent and level of MSI and the age of onset of carcinoma, suggesting differences in the rate of tumour progression. A high frequency of MSI in hyperplasias, found only in MSH2 mutation carriers, might indicate a more rapid tumour progression, correlating with an earlier age of onset of carcinoma. The present study indicates that assessment of altered protein staining combined with MSI analysis of endometrial tumours might direct the mutational analysis of MMR genes.