RESUMEN
BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer but remains underdiagnosed. Large prospective observational studies have recently increased understanding of the effectiveness of colonoscopic surveillance and the heterogeneity of cancer risk between genotypes. The need for gene- and gender-specific guidelines has been acknowledged. METHODS: The European Hereditary Tumour Group (EHTG) and European Society of Coloproctology (ESCP) developed a multidisciplinary working group consisting of surgeons, clinical and molecular geneticists, pathologists, epidemiologists, gastroenterologists, and patient representation to conduct a graded evidence review. The previous Mallorca guideline format was used to revise the clinical guidance. Consensus for the guidance statements was acquired by three Delphi voting rounds. RESULTS: Recommendations for clinical and molecular identification of Lynch syndrome, surgical and endoscopic management of Lynch syndrome-associated colorectal cancer, and preventive measures for cancer were produced. The emphasis was on surgical and gastroenterological aspects of the cancer spectrum. Manchester consensus guidelines for gynaecological management were endorsed. Executive and layperson summaries were provided. CONCLUSION: The recommendations from the EHTG and ESCP for identification of patients with Lynch syndrome, colorectal surveillance, surgical management of colorectal cancer, lifestyle and chemoprevention in Lynch syndrome that reached a consensus (at least 80 per cent) are presented.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Antiinflamatorios no Esteroideos/uso terapéutico , Aspirina/uso terapéutico , Quimioprevención , Colonoscopía , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Técnica Delphi , Procedimientos Quirúrgicos del Sistema Digestivo , Detección Precoz del Cáncer , Femenino , Tamización de Portadores Genéticos , Pruebas Genéticas , Neoplasias de los Genitales Femeninos/diagnóstico , Neoplasias de los Genitales Femeninos/genética , Humanos , Estilo de Vida , Procedimientos Quirúrgicos ProfilácticosRESUMEN
BACKGROUND: The severity of Tuberous Sclerosis Complex (TSC) can vary among affected individuals. Complications of TSC can be life threatening, with significant impact on patients' quality of life. Management may vary dependent on treating physician, local and national policies, and funding. There are no current UK guidelines. We conducted a Delphi consensus process to reach agreed guidance for the management of patients with TSC in the UK. METHODS: We performed a literature search and reviewed the 2012/13 international guideline for TSC management. Based on these, a Delphi questionnaire was formed. We invited 86 clinicians and medical researchers to complete an online survey in two rounds. All the people surveyed were based in the UK. Clinicians were identified through the regional TSC clinics, and researchers were identified through publications. In round one, 55 questions were asked. In round two, 18 questions were asked in order to obtain consensus on the outstanding points that had been contentious in round one. The data was analysed by a core committee and subcommittees, which consisted of UK experts in different aspects of TSC. The Tuberous Sclerosis Association was consulted. RESULTS: About 51 TSC experts took part in this survey. Two rounds were required to achieve consensus. The responders were neurologists, nephrologists, psychiatrist, psychologists, oncologists, general paediatricians, dermatologist, urologists, radiologists, clinical geneticists, neurosurgeons, respiratory and neurodisability clinicians. CONCLUSIONS: These new UK guidelines for the management and surveillance of TSC patients provide consensus guidance for delivery of best clinical care to individuals with TSC in the UK.
Asunto(s)
Esclerosis Tuberosa/epidemiología , Esclerosis Tuberosa/terapia , Humanos , Vigilancia de la Población , Calidad de Vida , Encuestas y Cuestionarios , Reino Unido/epidemiologíaRESUMEN
Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.
Asunto(s)
Ceguera/genética , Mutación , Fosfolipasas/genética , Fosfolipasas/fisiología , Secuencia de Aminoácidos , Animales , Niño , Preescolar , Drosophila , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Datos de Secuencia Molecular , Linaje , Fenotipo , Fosfolípidos/química , Retina/patología , Degeneración Retiniana/genética , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Tuberous sclerosis (TSC) is an inherited syndrome in which tumours in multiple organs are characterised by activation of mammalian target of rapamycin complex 1 (mTORC1). Previous work suggests that mTORC1 activation is associated with feedback inhibition of Akt, a substrate of mTORC2. This could limit TSC-associated tumour growth but lead to paradoxical promotion of tumour cell survival upon treatment with mTOR inhibitors. However, Akt/mTOR signalling has not been fully investigated in TSC-associated tumours and it has been uncertain whether mTOR inhibition can prevent TSC-associated renal tumourigenesis. In this study, we investigated Akt/mTOR signalling in renal tumours using a Tsc2(+/-) mouse model and tested whether mTOR inhibition could prevent renal tumourigenesis. We found that all renal lesions including cysts, adenomas and carcinomas exhibited activation of both Akt and mTORC1 as evidenced by increased protein expression and phosphorylation of Akt and mTOR and their downstream targets. Protein kinase Cα was also highly expressed and phosphorylated in these lesions, consistent with activation of mTORC2. Surprisingly, IRS proteins were highly expressed, in contrast to a striking decrease seen in cultured Tsc2(-/-) mouse embryonic fibroblasts, suggesting one mechanism through which loss of feedback inhibition of Akt may occur in mTORC1 hyperactivated Tsc-associated tumours. Long-term treatment with rapamycin reduced both Akt and mTORC1 activity in normal kidney tissues and blocked the development of all types of renal lesions. In conclusion, in contrast to previous studies, we found that Akt signalling is not inhibited in Tsc-associated renal lesions and that by partially inhibiting the Akt/mTOR pathway, rapamycin is highly effective in preventing Tsc-associated tumours.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Neoplasias Renales , Neoplasias Experimentales , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Proteínas Supresoras de Tumor , Animales , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/prevención & control , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Ratones , Ratones Mutantes , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Neoplasias Experimentales/genética , Neoplasias Experimentales/metabolismo , Neoplasias Experimentales/patología , Neoplasias Experimentales/prevención & control , Fosforilación/efectos de los fármacos , Fosforilación/genética , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/genética , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Recent clinical trials using rapalogues in tuberous sclerosis complex show regression in volume of typically vascularised tumours including angiomyolipomas and subependymal giant cell astrocytomas. By blocking mechanistic/mammalian target of rapamycin complex 1 (mTORC1) signalling, rapalogue efficacy is likely to occur, in part, through suppression of hypoxia-inducible factors (HIFs) and vascular endothelial growth factors (VEGFs). We show that rapamycin reduces HIF-1α protein levels, and to a lesser extent VEGF-A levels, in renal cystadenoma cells in a Tsc2+/- mouse model. We established that mTORC1 drives HIF-1α protein accumulation through enhanced transcription of HIF-1α mRNA, a process that is blocked by either inhibition or knockdown of signal transducer and activation of transcription 3 (STAT3). Furthermore, we demonstrated that STAT3 is directly phosphorylated by mTORC1 on Ser727 during hypoxia, promoting HIF-1α mRNA transcription. mTORC1 also regulates HIF-1α synthesis on a translational level via co-operative regulation of both initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase-1 (S6K1), whereas HIF-1α degradation remains unaffected. We therefore proposed that mTORC1 drives HIF-1α synthesis in a multifaceted manner through 4E-BP1/eIF4E, S6K1 and STAT3. Interestingly, we observed a disconnect between HIF-1α protein levels and VEGF-A expression. Although both S6K1 and 4E-BP1 regulate HIF-1α translation, VEGF-A is primarily under the control of 4E-BP1/eIF4E. S6K1 inhibition reduces HIF-1α but not VEGF-A expression, suggesting that mTORC1 mediates VEGF-A expression via both HIF-1α-dependent and -independent mechanisms. Our work has important implications for the treatment of vascularised tumours, where mTORC1 acts as a central mediator of STAT3, HIF-1α, VEGF-A and angiogenesis via multiple signalling mechanisms.
Asunto(s)
Proteínas Portadoras/metabolismo , Cistadenocarcinoma/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/metabolismo , Complejos Multiproteicos/metabolismo , Proteínas de Neoplasias/metabolismo , Fosfoproteínas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Hipoxia de la Célula/genética , Cistadenocarcinoma/genética , Cistadenocarcinoma/patología , Factores Eucarióticos de Iniciación , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Neoplasias Renales/genética , Neoplasias Renales/patología , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Ratones Noqueados , Complejos Multiproteicos/genética , Proteínas de Neoplasias/genética , Fosfoproteínas/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Factor de Transcripción STAT3/genética , Serina-Treonina Quinasas TOR/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Molecular characteristics of cancer vary between individuals. In future, most trials will require assessment of biomarkers to allocate patients into enriched populations in which targeted therapies are more likely to be effective. The MRC FOCUS3 trial is a feasibility study to assess key elements in the planning of such studies. PATIENTS AND METHODS: Patients with advanced colorectal cancer were registered from 24 centres between February 2010 and April 2011. With their consent, patients' tumour samples were analysed for KRAS/BRAF oncogene mutation status and topoisomerase 1 (topo-1) immunohistochemistry. Patients were then classified into one of four molecular strata; within each strata patients were randomised to one of two hypothesis-driven experimental therapies or a common control arm (FOLFIRI chemotherapy). A 4-stage suite of patient information sheets (PISs) was developed to avoid patient overload. RESULTS: A total of 332 patients were registered, 244 randomised. Among randomised patients, biomarker results were provided within 10 working days (w.d.) in 71%, 15 w.d. in 91% and 20 w.d. in 99%. DNA mutation analysis was 100% concordant between two laboratories. Over 90% of participants reported excellent understanding of all aspects of the trial. In this randomised phase II setting, omission of irinotecan in the low topo-1 group was associated with increased response rate and addition of cetuximab in the KRAS, BRAF wild-type cohort was associated with longer progression-free survival. CONCLUSIONS: Patient samples can be collected and analysed within workable time frames and with reproducible mutation results. Complex multi-arm designs are acceptable to patients with good PIS. Randomisation within each cohort provides outcome data that can inform clinical practice.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Medicina de Precisión , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Neoplasias Colorrectales/mortalidad , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras) , Resultado del TratamientoRESUMEN
The lymphedema-lymphangiectasia-intellectual disability (Hennekam) syndrome (HS) is characterised by a widespread congenital lymph vessel dysplasia manifesting as congenital lymphedema of the limbs and intestinal lymphangiectasia, accompanied by unusual facial morphology, variable intellectual disabilities and infrequently malformations. The syndrome is heterogeneous as mutations in the gene CCBE1 have been found responsible for the syndrome in only a subset of patients. We investigated whether it would be possible to predict the presence of a CCBE1 mutation based on phenotype by collecting clinical data of patients diagnosed with HS, with or without a CCBE1 mutation. We report here the results of 13 CCBE1 positive patients, 16 CCBE1 negative patients, who were clinically found to have classical HS, and 8 patients in whom the diagnosis was considered possible, but not certain, and in whom no CCBE1 mutation was identified. We found no statistically significant phenotypic differences between the 2 groups with the clinical HS phenotype, although the degree of lymphatic dysplasia tended to be more pronounced in the mutation positive group. We also screened 158 patients with less widespread and less pronounced forms of lymphatic dysplasia for CCBE1 mutations, and no mutation was detected in this group. Our results suggest that (1) CCBE1 mutations are present only in patients with a likely clinical diagnosis of HS, and not in patients with less marked forms of lymphatic dysplasia, and (2) that there are no major phenotypic differences between HS patients with or without CCBE1 mutations.
RESUMEN
BACKGROUND AND AIM: MUTYH-associated polyposis (MAP) is an autosomal recessive inherited disorder characterised by the development of polyposis in the upper and lower gastrointestinal tract and a high risk of colorectal cancer (CRC). We evaluated the natural history of the disease and the outcome of colorectal surveillance and management. METHODS: A large Western European dataset of biallelic MUTYH mutation carriers comprising 254 patients was used. Detailed information was collected on polyp and cancer development in the colorectum, and the outcome of surveillance and surgery. Survival methods were used to calculate the risk of CRC development. RESULTS: The mean follow-up was 9.8 years. Colorectal polyposis was diagnosed at a mean age of 44.8 years (range: 12-77 years). Most patients had <100 colorectal adenomas at diagnosis. CRC was diagnosed in 147 (58%) of the 254 patients (mean age at diagnosis: 48.5, range: 21-77 years). The cumulative lifetime risk of CRC was 63% at age 60 years. There was no correlation between the number of adenomas and the presence of CRC. The cumulative risk of CRC in patients presenting with polyps was 9% after 5 years of follow-up. Patients presenting with CRC had 11% risk of developing a metachronous CRC at 5 years after surgery. Thirty-seven per cent of patients with MAP with CRC who underwent partial colonic resection needed secondary surgery shortly afterwards. CONCLUSIONS: The high risk of developing CRC under surveillance in patients with MAP may suggest an accelerated carcinogenesis. Surveillance of these patients should therefore include colonoscopy at short intervals, for example, at 1-2-year intervals starting from the age of 18 to 20 years. If surgery for CRC is warranted, a (sub)total colectomy is recommended.
Asunto(s)
Adenoma/patología , Neoplasias Colorrectales/patología , ADN Glicosilasas/genética , Progresión de la Enfermedad , Poliposis Intestinal/patología , Adenoma/genética , Adenoma/cirugía , Adolescente , Adulto , Anciano , Niño , Colectomía , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Marcadores Genéticos , Mutación de Línea Germinal , Humanos , Poliposis Intestinal/genética , Poliposis Intestinal/cirugía , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Reoperación , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
Asunto(s)
Síndrome de Peutz-Jeghers/diagnóstico , Adulto , Anciano , Neoplasias de la Mama/diagnóstico , Niño , Preescolar , Endoscopía Gastrointestinal , Medicina Basada en la Evidencia/métodos , Femenino , Neoplasias Gastrointestinales/diagnóstico , Neoplasias de los Genitales Femeninos/diagnóstico , Genotipo , Humanos , Cuidados a Largo Plazo/métodos , Masculino , Tamizaje Masivo/métodos , Persona de Mediana Edad , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Fenotipo , Vigilancia de la Población/métodos , Adulto JovenRESUMEN
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.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Reparación de la Incompatibilidad de ADN , Europa (Continente)/epidemiología , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Directrices para la Planificación en Salud , Humanos , Anamnesis , Proteína 2 Homóloga a MutS/genética , Mutación , Linaje , Factores de RiesgoRESUMEN
BACKGROUND: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage. OBJECTIVES: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype. METHODS: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in approximately 300 population controls. RESULTS: Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases. CONCLUSION: Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , ADN Glicosilasas/genética , Predisposición Genética a la Enfermedad , Mutación , Proteínas de Neoplasias/genética , Adolescente , Adulto , Anciano , Alelos , Enzimas Reparadoras del ADN/genética , Desoxirribonucleasa (Dímero de Pirimidina)/genética , Genes Recesivos , Humanos , Persona de Mediana Edad , Fenotipo , Monoéster Fosfórico Hidrolasas/genética , Reacción en Cadena de la Polimerasa/métodos , Sistema de RegistrosRESUMEN
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.
Asunto(s)
Poliposis Adenomatosa del Colon/terapia , Poliposis Adenomatosa del Colon/diagnóstico , Poliposis Adenomatosa del Colon/genética , Edad de Inicio , Antiinflamatorios no Esteroideos/uso terapéutico , Neoplasias Duodenales/diagnóstico , Neoplasias Duodenales/terapia , Femenino , Fibromatosis Agresiva/diagnóstico , Fibromatosis Agresiva/terapia , Genes APC , Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Humanos , Masculino , Factores de RiesgoRESUMEN
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.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis/terapia , Guías de Práctica Clínica como Asunto , Colon/patología , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Endometriales/epidemiología , Europa (Continente)/epidemiología , Femenino , Pruebas Genéticas , HumanosRESUMEN
MAP (MutYH-associated polyposis) is a recently described colorectal adenoma and carcinoma predisposition syndrome that is associated with biallelic-inherited mutations of the human MutY homologue gene, MutYH. MutYH is often also termed MYH. MAP tumours display a mutational signature of somatic guanine-to-thymine transversion mutations in the adenomatous polyposis coli and K-ras genes, reflecting the normal role of MutYH in the base excision repair of adenines misincorporated opposite 7,8-dihydro-8-oxoguanine, a prevalent and stable product of oxidative damage to DNA. However, the full genetic pathway of MAP tumorigenesis has not been elucidated.
Asunto(s)
Poliposis Adenomatosa del Colon/genética , Neoplasias Colorrectales/genética , ADN Glicosilasas/genética , Mutación , Disparidad de Par Base/genética , Daño del ADN , HumanosRESUMEN
Colorectal tumours from MYH polyposis patients display an excess of somatic G : C --> T : A transversions in the adenomatous polyposis coli gene. Here, we identify k-ras mutations in nine out of 54 (16.7%) MYH polyposis tumours. Their presence was associated with increased dysplasia and tubulovillous morphology (P=0.005). G : C --> T : A transversions in k-ras were significantly more frequent in MYH polyposis adenomas than in sporadic or familial adenomatous polyposis-associated tumours (PAsunto(s)
Adenoma/genética
, Poliposis Adenomatosa del Colon/genética
, Carcinoma/genética
, Neoplasias Colorrectales/genética
, Genes ras
, Mutación de Línea Germinal
, Adenoma/patología
, Poliposis Adenomatosa del Colon/patología
, Carcinoma/patología
, Neoplasias Colorrectales/patología
, Análisis Mutacional de ADN
, Humanos
, Reacción en Cadena de la Polimerasa
Asunto(s)
Trastornos Mentales/complicaciones , Trastornos Mentales/genética , Proteínas/genética , Proteínas Represoras/genética , Esclerosis Tuberosa/genética , Esclerosis Tuberosa/psicología , Ansiedad/complicaciones , Ansiedad/genética , Trastorno Autístico/complicaciones , Trastorno Autístico/genética , Genotipo , Humanos , Lactante , Inteligencia/genética , Pruebas de Inteligencia , Modelos Logísticos , Mutación/genética , Fenotipo , Espasmos Infantiles/complicaciones , Espasmos Infantiles/genética , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/fisiopatología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorRESUMEN
The tuberous sclerosis complex genes TSC1 and TSC2 were first identified by positional cloning strategies in the heritable human disorder tuberous sclerosis. They encode previously unknown proteins, termed hamartin and tuberin respectively, that form a functional complex. The phenotypic manifestations of tuberous sclerosis are extremely diverse and suggest normal roles for TSC1 and TSC2 in regulating the growth, proliferation, migration and differentiation of many cell types. Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected. Most promisingly, the hamartin-tuberin complex has been shown to function as a negtive regulator of the insulin receptor/phosphoinositide 3-kinase/S6 kinase pathway. Drugs that act to inhibit this pathway may have therapeutic potential for tuberous sclerosis and the related disorder lymphangioleiomyomatosis.
Asunto(s)
Hamartoma/genética , Mutación , Proteínas/genética , Proteínas Represoras/genética , Esclerosis Tuberosa/genética , Animales , Diferenciación Celular , Drosophila/genética , Genes Letales , Genes Supresores de Tumor , Mutación de Línea Germinal , Humanos , Proteínas/metabolismo , Proteínas Represoras/metabolismo , Esclerosis Tuberosa/patología , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorAsunto(s)
Síndrome de Beckwith-Wiedemann/etiología , Técnicas Reproductivas Asistidas/efectos adversos , Síndrome de Beckwith-Wiedemann/genética , Estudios de Cohortes , Femenino , Fertilización In Vitro/efectos adversos , Fertilización In Vitro/estadística & datos numéricos , Impresión Genómica/genética , Humanos , Parto , Técnicas Reproductivas Asistidas/estadística & datos numéricos , Inyecciones de Esperma Intracitoplasmáticas/efectos adversos , Inyecciones de Esperma Intracitoplasmáticas/estadística & datos numéricosRESUMEN
Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2 genes, are likely to be closely linked. The proteins interact directly with one another and mutations affecting either gene result in the tuberous sclerosis phenotype. However, the regions of hamartin and tuberin that interact have not been well defined, and the relationship between their interaction and the pathogenesis of tuberous sclerosis has not been explored. To address these issues a series of hamartin and tuberin constructs were used to assay for interaction in the yeast two-hybrid system. Hamartin (amino acids 302-430) and tuberin (amino acids 1-418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346-371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719-998) predicted to encode coiled-coils was capable of oligermerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin (N198_F199delinsI;593-595delACT) or tuberin (G294E and I365del), abolished or dramatically reduced interaction of the proteins as assessed by yeast two-hybrid assays and by co-immunoprecipitation of the full-length proteins from Cos7 cells. In contrast, three non-pathogenic missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same region as the disease-causing TSC2 mutations did not. These results indicate a requirement for interaction in critical growth suppressing functions of hamartin and tuberin.