2,601 research outputs found
Revised guidelines for the clinical management of Lynch syndrome (HNPCC): recommendations by a group of European experts
No full textLynch syndrome (LS) 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. In 2007, a group of European experts (the Mallorca group) published guidelines for the clinical management of LS. Since then substantial new information has become available necessitating an update of the guidelines. In 2011 and 2012 workshops were organised in Palma de Mallorca. A total of 35 specialists from 13 countries participated in the meetings. The first step was to formulate important clinical questions. Then a systematic literature search was performed using the Pubmed database and manual searches of relevant articles. During the workshops the outcome of the literature search was discussed in detail. The guidelines described in this paper may be helpful for the appropriate management of families with LS. Prospective controlled studies should be undertaken to improve further the care of these families
Novel MSH2 Mutation in the First Report of a Vietnamese–American Kindred with Lynch Syndrome
No full text•First report of Lynch syndrome in a Vietnamese kindred•A novel MSH2 mutation has been identified.•Culturally sensitive screening programs need to be developed in this growing population
Absence of germline mutations in exons 5-9 of the p53 gene in patients with Li-Fraumeni-like (SBLA) and familial adenomatous polyposis heritable cancer syndromes.
No full textAlthough acquired mutations in the human p53 gene occur in many tumor types, germline mutations are rare. An exception is the occurrence of germline p53 mutations in a fraction of families afflicted with the Li-Fraumeni syndrome (LFS). Previous studies from our laboratory demonstrated increased levels of wild type p53 protein in skin fibroblasts (SF) of patients from heritable cancer syndrome, including familial adenomatous polyposis (FAP), neurofibromatosis type 1 (NF1), and bilateral retinoblastoma (bRB) (Kopelovich and DeLeo, 1984,1986). Here, we further address the association between germline p53 alterations and genetic predisposition to cancer in the SBLA syndrome and in FAP. DNA sequencing and single-stranded conformational polymorphism analysis (SSCP) were utilized to screen for the presence of mutations within exons 5-9 of the p53 gene in SF and in benign tumors. Thus we observed no germline mutations in exons 5-9 of the p53 gene in SF from SBLA or FAP patients, including the Gardner variant. In addition, we observed no acquired mutations in exons 5-9 of the p53 gene in benign tumors from FAP patients. In conclusion, we found no association between germline p53 mutations and SBLA or FAP. How mechanisms that involve nonmutational activation of the p53 protein might affect genetic predisposition to cancer remains to be established
Caracterització i identificació de les formes hereditàries de càncer colorectal
No full text[cat] El càncer colorectal (CCR) és una de les neoplàsies més prevalents en els països occidentals, i un dels tumors en el que els factors genètics juguen un paper fonamental en el seu desenvolupament. Així, l'anomenat CCR hereditari, entès com aquelles formes degudes a l'alteració de gens d'alta penetrança, suposa entre el 3-5% de tots els casos. Tot i que suposen un percentatge baix de forma global, l'elevada prevalença del CCR, i les conseqüències catastròfiques de les síndromes hereditàries, converteixen el diagnòstic d'aquestes malalties en un objectiu fonamental a la pràctica clínica, justificant la creació d'unitats específiques. El diagnòstic d'una síndrome hereditària té conseqüències potencialment beneficioses, no només pel pacient, sinó també pels familiars, podent realitzar un diagnòstic presimptomàtic. Per tant, el primer pas consisteix en identificar als individus o pacients que potencialment poden tenir una malaltia hereditària, per tal de poder realitzar en ells els estudis moleculars necessaris pel diagnòstic. Les síndromes hereditàries associades al CCR es divideixen des d'un punt de vista fenotípic en síndromes polipòsiques, com la poliposi adenomatosa familiar, i en síndromes no polipòsiques, encapçalades per la síndrome de Lynch, algunes formes de CCR associat al gen MYH i l'anomenat CCR hereditari tipus X. Mentre que a la pràctica clínica el diagnòstic de les síndromes polipòsiques és senzill donada la seva expressivitat clínica, el diagnòstic de les formes no polipòsiques representa un repte constant pel clínic, donat que en moltes ocasions el fenotip pot ser indistingible del CCR esporàdic. La síndrome de Lynch constitueix la forma més freqüent de CCR hereditari. L'estratègia diagnostica es basa en els criteris revisats de Bethesda, que tenen com objectiu identificar aquells pacients amb una major probabilitat de ser portadors d'una mutació germinal als gens reparadors de l'ADN, en els que estaria indicat avaluar la presència d'alteració del sistema de reparació de l'ADN en el tumor mitjançant l'estudi d'inestabilitat de microsatèl.lits o tinció per immunohistoquímica de les proteïnes reparadores de l'ADN. Encara que aquests criteris han demostrat ser una estratègia efectiva, han estat àmpliament criticats degut a la seva complexitat, i la necessitat d'avaluar el tumor, que en ocasions no és possible. Recentment, han aparegut diferents models predictius de mutació germinal en els gens reparadors de l'ADN, basats en la història personal, familiar i molecular. Aquests models, entre els que es troba l'anomenat PREMM1,2, ofereixen una aproximació quantitativa de la probabilitat de ser portador de mutacions, de forma que en funció de la magnitud d'aquesta, l'actitud preventiva i l'estratègia molecular podria ser diferent. No obstant, l'avaluació d'aquests models en una sèrie de pacients amb CCR de base poblacional no s'ha realitzat fins el moment. Per altra banda, el CCR associat al gen MYH és una síndrome de recent descripció, en el que a diferència de la síndrome de Lynch, la informació de les manifestacions fenotípiques i el risc de CCR associat a la presència de mutacions és molt reduïda. Així, tot i que els pacients amb mutacions bial.lèliques solen presentar una forma de poliposi adenomatosa, fins en un 30% no presenten adenomes associats al CCR. A més, el risc de CCR associat a mutacions monoal.lèliques és controvertit. Basant-se en el projecte EPICOLON, un estudi multicèntric de base poblacional que va recollir tots els pacients amb CCR incidents a Espanya durant els anys 2000-2001, la present tesi doctoral aprofundeix en la caracterització i identificació de la síndrome de Lynch i el CCR associat al gen MYH, aportant informació rellevant i novedosa al respecte.[eng] Colorectal cancer (CRC) is the second most common cancer in most developed countries. AColorectal cancer (CRC) is the second most common cancer in most developed countries. Although it is assumed that up to 20-25% of cases develop as a result of inherited genetic factors, known genes predisposing to this malignancy account for less than 5%. Hereditary CRC is traditionally divided into polyposic syndromes, such as familial adenomatous polyposis, and non polyposic syndromes, such as Lynch syndrome. Early diagnosis of these hereditary forms is crucial since intensive cancer screening and prophylactic surgery have been shown to reduce the incidence and mortality of CRC. Moreover, appropriate presymptomatic testing can be offered to reduce mortality among at-risk family members, and relatives not at risk can avoid unnecessary intensive surveillance. However, heterogeneity of non polyposic syndromes complicates early recognition, which is critical and often difficult. In parallel with this difficulty, diagnostic criteria continue to evolve as understanding and characterization of these syndromes improve. Indeed, identification of Lynch syndrome can be done by molecular pre-screening using microsatellite instability analysis and/or immunostaining in combination or not with clinical criteria. Nevertheless, Lynch syndrome identification is moving toward more refined algorithms and multivariable models which combine personal and familial data in order to obtain a quantitative estimation of the risk. Following this direction, the PREMM1,2 model provides a new and easy-to-use model to predict mutations in the MLH1/MSH2 genes. Whereas the model accurately discriminates gene mutation carriers in the subset of individuals at moderate to high risk for Lynch syndrome, its usefulness in an unselected CRC population is unknown. Furthermore, efficacy of the PREMM1,2 model in combination with tumor MMR testing has not yet been assessed. On the other hand, whereas it has conclusively demonstrated that biallelic MYH mutations confer a significant risk for colorectal cancer (CRC), the influence of monoallelic mutations remains controversial. In this sense, characterization of MYH-associated CRC is critical to identify individuals who may benefit from preventive strategies.Using data from the EPICOLON study, a prospective, multicenter, population-based cohort of CRC patients in Spain, the present Doctoral Thesis study in depth the characterization and identification of non polyposic hereditary colorectal syndromes.lthough it is assumed that up to 20-25% of cases develop as a result of inherited genetic factors, known genes predisposing to this malignancy account for less than 5%. Hereditary CRC is traditionally divided into polyposic syndromes, such as familial adenomatous polyposis, and non polyposic syndromes, such as Lynch syndrome. Early diagnosis of these hereditary forms is crucial since intensive cancer screening and prophylactic surgery have been shown to reduce the incidence and mortality of CRC. Moreover, appropriate presymptomatic testing can be offered to reduce mortality among at-risk family members, and relatives not at risk can avoid unnecessary intensive surveillance. However, heterogeneity of non polyposic syndromes complicates early recognition, which is critical and often difficult. In parallel with this difficulty, diagnostic criteria continue to evolve as understanding and characterization of these syndromes improve. Indeed, identification of Lynch syndrome can be done by molecular pre-screening using microsatellite instability analysis and/or immunostaining in combination or not with clinical criteria. Nevertheless, Lynch syndrome identification is moving toward more refined algorithms and multivariable models which combine personal and familial data in order to obtain a quantitative estimation of the risk. Following this direction, the PREMM1,2 model provides a new and easy-to-use model to predict mutations in the MLH1/MSH2 genes. Whereas the model accurately discriminates gene mutation carriers in the subset of individuals at moderate to high risk for Lynch syndrome, its usefulness in an unselected CRC population is unknown. Furthermore, efficacy of the PREMM1,2 model in combination with tumor MMR testing has not yet been assessed. On the other hand, whereas it has conclusively demonstrated that biallelic MYH mutations confer a significant risk for colorectal cancer (CRC), the influence of monoallelic mutations remains controversial. In this sense, characterization of MYH-associated CRC is critical to identify individuals who may benefit from preventive strategies.Using data from the EPICOLON study, a prospective, multicenter, population-based cohort of CRC patients in Spain, the present Doctoral Thesis study in depth the characterization and identification of non polyposic hereditary colorectal syndromes
Càncer colorectal hereditari: Aplicacions diagnòstiques de l'estudi de la dosi dels gens APC, MLH1 i MSH2
No full text[cat] Les síndromes de càncer colorectal (CCR) hereditari representen entre un 3% i un 5% de tots els casos de CCR i inclouen tots aquells individus amb un elevat grau d'agregació familiar. La més freqüent és la síndrome de Lynch, causada per la presència de mutacions en els gens reparadors del DNA, majoritàriament MLH1 i MSH2. La poliposi adenomatosa familiar (FAP) és la segona en incidència, es caracteritza per l'aparició de pòlips precursors a la neoplàsia colorectal i la seva causa principal és la presència de mutacions en el gen supressor tumoral APC. En els últims anys s'ha descobert que els grans reordenaments d'aquests gens són responsables de la malaltia en una part de les famílies que pateixen aquestes síndromes. A més, estudis d'expressió d'aquests gens en línia germinal han demostrat l'existència de desequilibris al·lèlics tant en famílies portadores de mutacions com en famílies on no es detecten mutacions en el DNA. L'objectiu d'aquesta tesi és l'estudi de la dosi en la dels gens MLH1, MSH2 i APC, implicats en la síndrome de Lynch i la FAP. D'aquesta forma, hem analitzat la dosi tant a nivell de DNA (grans reordenaments) com a nivell d'RNA (expressió específica d'al·lel), sempre treballant amb línia germinal de pacients. Els resultats aquí recollits permeten millorar l'estratègia de diagnòstic molecular de les famílies amb síndrome de Lynch i FAP que són ateses al nostre centre, al mateix temps que la comprensió del procés tumorogènic.[eng] Hereditary colorectal cancer (CRC) syndromes represent about 3% to 5% of all cases of CRC and include all those individuals with high familiar aggregation. The most frequent syndrome is Lynch syndrome, caused by the presence of mutations in the mismatch repair (MMR) genes, mostly MLH1 and MSH2. Familiar adenomatous polyposis (FAP) is the second in incidence, is characterized by precursor polyps and its mainly caused by mutations in the tumoral suppressor gene APC. Recently, it has been discovered that gross rearrangements of these genes are responsible of these two syndromes. Also, expression analyses of these genes in the germline have demonstrated the existence of allelic imbalances in both families carrying pathogenic mutations and families without detected mutations. Our aim was to study de dose of MLH1, MSH2 and APC genes in the germline of Lynch syndrome and polyposis families, respectively. To that end, we analyzed the dose at DNA level (gross rearrangements) and at RNA level (allele-specific expression) of these patients. The results summarized in this thesis permit improving the molecular diagnostic strategy in Lynch syndrome and FAP families, and also improve the knowledge of the tumorogenic process
Risk analysis of High-Temperature Aquifer Thermal Energy Storage (HT-ATES)
No full textThe storage of heat in aquifers, also referred to as Aquifer Thermal Energy Storage (ATES), bears a high potential to bridge the seasonal gap between periods of highest thermal energy demand and supply. With storage temperatures higher than 50 °C, High-Temperature (HT) ATES is capable to facilitate the integration of (non-)renewable heat sources into complex energy systems. While the complexity of ATES technology is positively correlated to the required storage temperature, HT-ATES faces multidisciplinary challenges and risks impeding a rapid market uptake worldwide. Therefore, the aim of this study is to provide an overview and analysis of these risks of HT-ATES to facilitate global technology adoption. Risk are identified considering experiences of past HT-ATES projects and analyzed by ATES and geothermal energy experts. An online survey among 38 international experts revealed that technical risks are expected to be less critical than legal, social and organizational risks. This is confirmed by the lessons learned from past HT-ATES projects, where high heat recovery values were achieved, and technical feasibility was demonstrated. Although HT-ATES is less flexible than competing technologies such as pits or buffer tanks, the main problems encountered are attributed to a loss of the heat source and fluctuating or decreasing heating demands. Considering that a HT-ATES system has a lifetime of more than 30 years, it is crucial to develop energy concepts which take into account the conditions both for heat sources and heat sinks. Finally, a site-specific risk analysis for HT-ATES in the city of Hamburg revealed that some risks strongly depend on local boundary conditions. A project-specific risk management is therefore indispensable and should be addressed in future research and project developments.Accepted Author ManuscriptWater Resource
C-terminal fluorescent labeling impairs functionality of DNA mismatch repair proteins
No full textThe human DNA mismatch repair (MMR) process is crucial to maintain the integrity of the genome and requires many different proteins which interact perfectly and coordinated. Germline mutations in MMR genes are responsible for the development of the hereditary form of colorectal cancer called Lynch syndrome. Various mutations mainly in two MMR proteins, MLH1 and MSH2, have been identified so far, whereas 55% are detected within MLH1, the essential component of the heterodimer MutLα (MLH1 and PMS2). Most of those MLH1 variants are pathogenic but the relevance of missense mutations often remains unclear. Many different recombinant systems are applied to filter out disease-associated proteins whereby fluorescent tagged proteins are frequently used. However, dye labeling might have deleterious effects on MutLα's functionality. Therefore, we analyzed the consequences of N- and C-terminal fluorescent labeling on expression level, cellular localization and MMR activity of MutLα. Besides significant influence of GFP- or Red-fusion on protein expression we detected incorrect shuttling of single expressed C-terminal GFP-tagged PMS2 into the nucleus and found that C-terminal dye labeling impaired MMR function of MutLα. In contrast, N-terminal tagged MutLαs retained correct functionality and can be recommended both for the analysis of cellular localization and MMR efficiency
Improving identification of HT-ATES performance drivers and -barriers
No full textHigh temperature aquifer thermal energy storage (HT-ATES) can potentially solve the mismatch between heat supply and demand. It can provide a large scale seasonal heat storage solution. Thereby it enables an increase in full load hours of the base heat source, which can benefit project performance on both costs and emissions. However, the limited number of successful pilot projects indicates the technology has not escaped its state of infancy. There is a gap from concept to implementation, which is signified by the disagreement of experts on performance drivers and barriers of HT-ATES. This research aims to narrow the described knowledge gap, by improving identification of HT-ATES performance drivers and barriers. Thereby it strives to improve decision making of HT-ATES implementation, and further enhance future HT-ATES application in heating projects. The broad scope of research demands both a diagnostic and design-orientated approach, and fits seamlessly with a multi-criteria decision analysis. The analysis entails the stages of creating, evaluating, comparing and ranking of case-specific scenarios. Parametric variation changes the conditions for HT-ATES implementation across the scenarios. A simulation model is developed and connected to a groundwater model to apply the parametric variation, to create the different scenarios, and consequently to produce the quantitative information for further evaluation. During the stages of creating, evaluating, comparing and ranking, the methodology systematically produces new results on the opportunities and risks introduced by HT-ATES, and additionally on the HT-ATES performance drivers and barriers. The results show that HT-ATES enables the opportunity of improving project performance with respect to the internal rate of return and emissions. Groundwater impact remains the greatest risk, but it can be minimised with smart decision making. To support the decision maker and to overcome the risk of groundwater impact, the research proposes several performance-enhancing, non-explicit guidelines. The guidelines focus on realising an HT-ATES implementation, where project performance with respect to internal rate of return, emissions and groundwater impact are balanced. Thereby they explain the major HT-ATES performance drivers and barriers. The guidelines are summarised below. The decision maker is recommended to .. 1. .. minimise the uncertainty, through thorough subsurface characterization before implementation. Secondly, to focus on aquifers with a minimum depth of 200 [m] and a minimum hydraulic conductivity of 5 [m/d] 2. .. assure network return temperatures during peak demand are below expected storage temperatures 3. .. not consider project life-times exceeding 20 years 4. .. assure yearly maximum base source heat production is always lower than yearly consumer heat demand 5. .. to strive for a flat demand curve and apply peak-shaving, by means of, for example, variable heat prices Currently, the guidelines have the purpose of giving direction to the decision maker, but they will become more explicit once the methodology is improved, and the uncertainty and number of assumptions in the model is decreased.Electrical Engineering | Sustainable Energy Technolog
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