Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

by Keung Wing Ying. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 115-128). / Abstract also in Chinese. / Abstract --- p.I / Acknowledgments --- p.IV / Abbreviations --- p.V / List of Tables --- p.VII / List of Figures --- p.VIII / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Familial Adenomatous Polyposis (FAP) --- p.1 / Chapter 1.1.1 --- Occurrence and prevalence --- p.1 / Chapter 1.1.2 --- Clinical features --- p.2 / Chapter 1.1.3 --- Laboratory studies --- p.5 / Chapter 1.1.4 --- Diagnosis --- p.6 / Chapter 1.1.5 --- Management --- p.8 / Chapter 1.2 --- Congenital Hypertrophy of the Retinal Pigment Epithelium (CHRPE) --- p.8 / Chapter 1.2.1 --- Clinical features --- p.9 / Chapter 1.2.2 --- Pathogenesis --- p.11 / Chapter 1.2.3 --- Histology --- p.12 / Chapter 1.2.4 --- Differential diagnosis --- p.13 / Chapter 1.2.5 --- CHRPE as an early clinical marker for FAP --- p.14 / Chapter 1.3 --- The Adenomatous Polyposis Coli (APC) Gene --- p.16 / Chapter 1.3.1 --- Discovery --- p.16 / Chapter 1.3.2 --- Structure and function --- p.17 / Chapter 1.3.3 --- Sequence alterations in the APC gene --- p.18 / Chapter 1.3.4 --- APC mutations associated with specific clinical features --- p.21 / Chapter 1.3.5 --- APC gene mutations in Chinese --- p.22 / Chapter 1.3.6 --- Methods for detecting mutation in the APC gene and linkage analysis --- p.23 / Chapter Chapter 2 --- Study Objectives --- p.44 / Chapter Chapter 3 --- Methodology --- p.45 / Chapter 3.1 --- Subjects --- p.45 / Chapter 3.2 --- CHRPE analysis --- p.45 / Chapter 3.2.1 --- Ophthalmoscopic examination --- p.45 / Chapter 3.2.2 --- Diagnostic criteria of CHRPE --- p.45 / Chapter 3.3 --- Materials and Equipment --- p.46 / Chapter 3.3.1 --- Enzymes --- p.46 / Chapter 3.3.2 --- DNA markers --- p.46 / Chapter 3.3.3 --- Reagent kits --- p.46 / Chapter 3.3.4 --- Primers for PCR --- p.46 / Chapter 3.3.5 --- Chemicals and reagents --- p.47 / Chapter 3.3.6 --- Radioisotopes --- p.47 / Chapter 3.3.7 --- Solutions and buffers --- p.47 / Chapter 3.3.8 --- Equipment --- p.48 / Chapter 3.4 --- Methods --- p.49 / Chapter 3.4.1 --- Blood collection --- p.49 / Chapter 3.4.2 --- DNA extraction --- p.49 / Chapter 3.4.3 --- DNA quantitation --- p.50 / Chapter 3.4.4 --- Polymerase Chain Reaction (PCR) --- p.50 / Chapter 3.4.5 --- Agarose gel electrophoresis --- p.51 / Chapter 3.4.6 --- Single Strand Conformation Polymorphism (SSCP) --- p.52 / Chapter 3.4.7 --- Direct DNA sequencing --- p.52 / Chapter 3.4.8 --- Analysis of microsatellite markers --- p.54 / Chapter Chapter 4 --- Results --- p.59 / Chapter 4.1 --- Study subjects --- p.59 / Chapter 4.1.1 --- FAP index patients --- p.59 / Chapter 4.1.2 --- FAP families --- p.59 / Chapter 4.1.3 --- Control subjects with CHRPE only --- p.60 / Chapter 4.1.4 --- Normal control subjects --- p.60 / Chapter 4.2 --- CHRPE analysis --- p.60 / Chapter 4.2.1 --- CHRPE in FAP index patients --- p.60 / Chapter 4.2.2 --- CHRPE in family members --- p.61 / Chapter 4.2.3 --- CHRPE in controls subjects --- p.61 / Chapter 4.2.4 --- Statistical analysis --- p.61 / Chapter 4.3 --- PCR optimization --- p.62 / Chapter 4.4 --- SSCP analysis of the APC gene --- p.62 / Chapter 4.5 --- Direct DNA sequencing analysis --- p.63 / Chapter 4.5.1 --- Nonsense mutations --- p.63 / Chapter 4.5.2 --- Novel silent mutations --- p.64 / Chapter 4.5.3 --- Polymorphisms --- p.65 / Chapter 4.6 --- Haplotype analysis --- p.67 / Chapter 4.7 --- Family studies --- p.67 / Chapter 4.7.1 --- Family A --- p.67 / Chapter 4.7.2 --- Family B --- p.68 / Chapter 4.7.3 --- Family C --- p.68 / Chapter 4.7.4 --- Family D --- p.69 / Chapter 4.7.5 --- Family E --- p.70 / Chapter 4.7.6 --- Family F --- p.70 / Chapter Chapter 5 --- Discussion --- p.104 / Chapter 5.1 --- The predictive value of CHRPE in FAP patients and family members --- p.104 / Chapter 5.2 --- The laboratory techniques in this study --- p.105 / Chapter 5.2.1 --- PCR optimization --- p.105 / Chapter 5.2.2 --- Single Strand Conformation Polymorphism (SSCP) --- p.106 / Chapter 5.2.3 --- Direct DNA sequencing --- p.107 / Chapter 5.3 --- Novel mutation in the APC gene --- p.108 / Chapter 5.4 --- Reported mutations in the APC gene --- p.108 / Chapter 5.4.1 --- 3183del5 --- p.108 / Chapter 5.4.2 --- R216X and R283X --- p.109 / Chapter 5.5 --- Novel silent mutations and polymorphisms in the APC gene --- p.109 / Chapter 5.5.1 --- Novel silent mutations --- p.109 / Chapter 5.5.2 --- Polymorphisms --- p.110 / Chapter 5.6 --- The relationship between APC gene mutations and CHRPE --- p.111 / Chapter 5.7 --- Haplotype analysis --- p.112 / Chapter Chapter 6 --- Conclusion --- p.114 / Chapter Chapter 7 --- References --- p.115

Thesis (Ph. D.)--University of Washington, 2008. / Vita. Includes bibliographical references (leaves 94-105).

Mutations in the tumour suppressor gene Adenomatous polyposis coli (APC) are found in 80 % of sporadic colorectal cancer (CRC) tumours and are also responsible for the inherited form of CRC, Familial adenomatous polyposis (FAP). In order to identify novel therapeutic targets for the treatment of APC mutated CRC, we have generated an in vitro model of APC mutant CRC using CRISPR-cas9 gene editing. Using the APC wildtype colorectal carcinoma cell line RKO, we targeted the cells with guide RNA (gRNA) targeting exon 2 or exon 15 (encodes 80 % of APC) of the APC gene. We generated isogenic cell lines which differed in the expression of APC, the controls were APC wildtype and the APC mutant (APC Lys736fs) cell lines expressed a truncated ~80 kDa APC protein. We used these cell lines to perform an siRNA screen against 720 kinases and kinase-related genes. We selected seven genes to investigate further, unfortunately none of the potential hits validated. Additionally, we performed an FDA-approved compound screen targeting over 1000 compounds. From this, we identified a group of HMG-CoA reductase (HMGCR) inhibitors known as statins, which selectively cause a greater loss in cell viability in the APC mutated cell lines, compared to the APC wildtype cells. Mechanistically, our data suggests this synthetic lethal relationship is due to a greater decrease in the anti-apoptotic protein survivin. We propose this is due to statins altering the localisation of Rac1, reducing Pak1 activation and reducing the level of Wnt signalling. This results in the reduction of the Wnt target gene survivin. We have successfully identified an FDA-approved family of compounds, which show synthetic lethality with the APC mutation in our in vitro model.

Der Tumorsupressor APC ist in der Mehrzahl aller Fälle kolorektaler Karzinome bereits in der initialen Phase der Karzinogenese mutiert. Diese Mutationen führen zu einer aberranten Aktivierung des Wnt-Signalweges sowie zu weiteren die Karzinogenese vorrantreibenden Aktivitäten, beispielsweise einem veränderten Migrationsverhalten. Dieser Dissertation zu Grunde liegt die Idee, dass durch die Trunkierung des APC-Proteins aber auch Abhängigkeiten von Genaktivitäten entstehen, die zuvor entbehrlich waren. Solche synthetisch letalen Gene sollten in einem high-content shRNA-Screen gefunden werden. Für die Durchführung des Screens wurde ein von der SW480 Kolonkarzinomzelllinie abgeleitetes, isogenes Zellsystem generiert, welches durch Induktion mit Doxyzyklin das vollständige APC-Allel (FL-APC) exprimiert. Infolge dieser Expression zeigen die Zellen einen weniger malignen Phänotyp. Dies spiegelt sich darin wider, dass die Zellen durch FL-APC Expression in ihrer Wnt-Signalwegsaktivität eingeschränkt werden. Doxyzyklininduzierte Zellen sind schlechter in der Lage ohne Adhäsion zu proliferieren als nicht induzierte Zellen. Andererseits ist ihre Fähigkeit einem FKS-gradienten entlang zu migrieren verbessert. Der shRNA-Screen wurde mit der Decipher shRNA-Bibliothek durchgeführt. Diese enthält 27.500 verschiedene shRNAs mit Interferenzaktivität gegen 5.000 mRNAs, die potentiell pharmakologisch inhibierbare Proteine kodieren. Die besten zwei Kandidaten für eine synthetisch letale Interaktion mit trunkiertem APC, BCL2L1 und EIF2B5 wurden im Verlauf einer Masterarbeit bzw. direkt in dieser Disseration validiert. EIF2B5 zeigte in vitro nach Depletion durch unterschiedliche shRNAs einen di erentiellen Proliferationse ekt bei FL-APC induzierten im Vergleich zu kontrollbehandelten Zellen. Dieser di erentielle E ekt konnte in einem weiteren Modellsystem, SW480 Zellen mit konstitutiver FL-APC Expression, ebenfalls validiert werden. Durch Expression einer shRNA mit Aktivität gegen EIF2B5 werden in beiden Zellsystem die unfolded protein response (UPR) Gene DDIT3 und splXBP1 aktiviert. Interessanterweise werden durch die Expression von FL-APC diese Gene reprimiert. Im Promotor der EIF2B5-mRNA be ndet sich eine Bindestelle für MYC. Es ist denkbar, dass durch die Expression von FL-APC eine globale Veränderung der Genexpression vorgenommen wird, die einerseits eine Repression von EIF2B5 nach sich zieht aber andererseits eine hierdurch ausgelöste ER-Stress Antwort verhindert. Eine Inhibition von EIF2B5 ohne diese Adaption andererseits führt nach diesem Model zu einer UPR-aktivierten Apoptose. In einem zweiten Projekt wurde das überraschende Verhalten von Kolonkarzinomzellen untersucht, die nach Zugabe von BEZ235, einem dualen PI3K/mTOR Inhibitor, trotz gegenteiliger Erwartungen MYC-Proteinmengen erhöhen. Eine Repression wurde erwar- tet, weil die Inhibition von PI3K einerseits zu einer proteasomalen Destabiliserung und andererseits die mTOR Inhibition zu einer verringerten Synthese von MYC führen sollte. Während bereits gezeigt werden konnte, dass durch einen FOXO-vermittelten Mechanismus MAPK-abhängig die MYC-Expression verstärkt wird, wurde in dieser Dissertation die erwartete Translationsinhibition untersucht. BEZ235 inhibiert zwar CAP-abhängige Translation, das MYC Protein wird jedoch aufgrund einer IRES-vermittelten Translation weiterhin exprimiert. Silvestrol, ein Inhibitor der Helikase eIF4A andererseits interveniert mit CAP- und IRES-abhängiger Translation und kann die MYC-Proteinkonzentrationen verringern. Wir konnten zudem feststellen, dass die Applikation von Silvestrol auch in vivo möglich und wirksam ist und zudem tolleriert wird. Dies gibt Anlass zur Ho nung, dass eine Intervention der Translation auch im Menschen eine valide Strategie zur Behandlung MYC-getriebener Tumore sein könnte. / The tumorsupressor APC is mutated in initiating colorectal cancers. These mutations lead to an aberrant actiavation of the wnt-signaling pahtway and to further carcinogenic activities such as altered migration behaviour. The idea that novel dependencies upon previously expendable genes are generated through APC-mutations form the basis of this disseration. These so called synthetic lethal Genes were searched for harnessing a high content shRNA screen. We generated an isogenic cell system which was deviated from the colorectal cancer cell line SW480. These cells naturally express truncated APC. The generated system expresses a full-lenght allele upon doxycycline exposure. SW480 cells which are induced partially revert their malignancy. Ancorage independend growth is compromised and migration along a gradient of fetal calf serum is improved. The Decipher shRNA library was used for screening. It consists of 27.500 di erent shRNAs intefering with the activity of 5.000 genes which are potantially drugable. The two best candidates scoring as hits in the screen were EIF2B5 and BCL2L1. BCL2L1 was validated in a cooperating masterthesis and EIF2B5 could be validated in the course of this diseration. Following EIF2B5 depletion using di erent shRNA constructs, we were able to see di erential behaviour in pTRE-APC cells as well as in a second model system in which FL-APC was expressed constitutively. Interestingly an activation of the ER-Stress genes DDIT3 and splXBP1 can be seen after EIF2B5 depletion. These genes are repressed, when FL-APC ist expressed. The EIF2B5 promotor has a MYC-binding site and we speculate, that FL-APC expression induces a genetic program which represses EIF2B5 on the one hand, however prohibits the ER-Stress reaction which follows this trigger. Inhibtion of EIF2B5 without this global adaption in genexpression on the other side initiates UPR-mediated apoptosis. In a second project, the suprising behaviour of colon carcinoma cell lines, which upregulate MYC upon BEZ235 exposure was examined. The dual inhibitor was thought to downregulate MYC through its PI3K and mTOR inhibitory acitivites which were thought to destabilise and MYC and prohibit it's expression, respectively. Whereas former work could demonstrate a FOXO-mediated, MAPK-dependend positive MYC-gene expression clue the aim of this thesis was to analyse the expecte protein tranlational inhibition. Indeed, BEZ235 inhibits CAP-dependend translation, however the MYC protein is still translated through IRES-dependend translation. The eIF4A-inhibitor Silvestrol intervenes with both CAP- and IRES-dependend translation and can therefore reduce MYC protein levels

Les mutacions germinals d'elevada penetrància del gen APC que originen una proteïna truncada són les responsables de la majoria de casos de poliposi, mentre que les variants missense, que canvien un aminoàcid de la proteïna, es detecten en una minoria dels casos. S'han identificat diverses variants missense en el gen APC, però el seu potencial patogènic és encara motiu de controvèrsia, el què limita la utilitat de la seva detecció en el consell genètic. L'estudi de la presència de les variants en la població control i en les diferents poblacions de càncer colorectal (CCR) esporàdic i hereditari, juntament amb la realització d'anàlisis funcionals, podrien ajudar a conèixer l'impacte de les variants del gen APC en el desenvolupament del CCR. El nostre objectiu és determinar el significat funcional de les variants identificades en el gen APC en pacients afectes de poliposi adenomatosa familiar en relació al risc de desenvolupar CCR tant esporàdic com hereditari.L'anàlisi molecular de la regió codificant del gen APC realitzat en 138 famílies amb poliposi adenomatosa familiar clàssica (n= 98) i poliposi adenomatosa familiar atenuada (n= 40) ha permès la identificació de deu variants missense del gen APC: G101E, K957N, N1026S, L1129S, I1307K, E1317Q, D1822V, A2274V, G2502S i P2681L. En el nostre estudi s'han caracteritzat amb diferent profunditat set d'aquestes deu variants: G101E, N1026S, L1129S, D1822V, A2274V, G2502S i P2681L. La variant APC G101E, identificada en una família de poliposi clàssica, no s'associa a la malaltia ni sembla tenir cap funció modificadora del fenotip de poliposi. L'efecte biològic de les variants APC A2274V i APC P2681L, identificades en dues famílies de poliposi, és encara desconegut. La variant APC G2502S és un polimorfisme que no sembla tenir rellevància clínica. La variant APC L1129S, identificada en dues famílies de poliposi, no altera la interacció de la proteïna APC 4x15 amb la beta-catenina. La variant APC D1822V és un polimorfisme que incrementa el risc de desenvolupar CCR en pacients amb història prèvia d'adenomes i no s'associa amb la història familiar de CCR. La variant APC N1026S, que està present de forma exclusiva en una família de poliposi adenomatosa familiar atenuada, disminueix la unió d'APC amb beta-catenina i activa moderadament la transcripció mitjançada pel complex beta-catenina/Tcf-4. Aquests resultats indiquen que la variant APC N1026S és patogènica i és la mutació responsable del desenvolupament de la poliposi atenuada a la família on es va identificar.La caracterització funcional de les variants del gen APC és de gran importància per conèixer la seva contribució en el desenvolupament de la poliposi i facilitar l'assessorament genètic. / Truncating germline mutations in the APC gene are responsible for the majority of Familial Adenomatous Polyposis (FAP) cases, while in a minority of cases missense mutations, leading to single amino acid changes, are detected. Germline missense variants in the APC gene have been reported although their contribution to FAP is controversial, limiting their use in genetic counseling. The aim of this thesis is to determine the functional relevance of the variants identified in the APC gene in FAP patients in order to establish its pathogenicity.The molecular analysis of the APC gene was performed in 138 classical (n= 98) and attenuated (n= 40) FAP families and allowed the identification of ten missense variants. In this thesis, seven out of these ten APC variants have been characterised: G101E, N1026S, L1129S, D1822V, A2274V, G2502S and P2681L. The APC G101E variant, identified in a classical FAP family, is not associated with the disease. The biological effect of APC A2274V and APC P2681L variants, identified in two FAP families, remains unknown. The APC G2502S variant is a polymorphism without clinical relevance. The APC L1129S variant, identified in two FAP families, does not modify the interaction of the APC 4x15 protein with beta-catenin. The APC D1822V variant is a polymorphism associated with an increased risk of adenoma transformation and does not associate with family history of colorectal cancer. The APC N1026S variant, identified for the first time in an attenuated FAP family, diminishes beta-catenin binding to APC and moderately activates beta-catenin/Tcf-4-mediated transcription. These findings strongly support a pathogenic role of the APC N1026S variant in the AFAP phenotype.In summary, functional characterization of APC variants is crucial to elucidate their contribution to FAP and improve genetic counseling.

Thesis (Ph.D.). / Written for the Dept. of Biomedical Engineering. Title from title page of PDF (viewed 2009/06/11). Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2004. / Vita. Includes bibliographical references (leaves 96-113).

Introdução: Pacientes com Polipose Adenomatosa Familiar (PAF) tem maior risco de desenvolvimento de carcinoma duodenal em comparação com a população em geral, sendo a classificação de Spigelman adotada como método de estadiamento da adenomatose duodenal em doentes com PAF. No entanto, a relação entre a gravidade da polipose duodenal e variáveis clínicas não é bem compreendida. Objetivos: 1) Avaliar, através do método endoscópico, a prevalência e a intensidade da adenomatose duodenojejunal em pacientes com PAF em nosso meio. 2) Verificar a associação de variáveis clínicas, com a gravidade fenotípica da adenomatose duodenal e ampular. Metodologia: Foram estudados prospectivamente, 62 pacientes com diagnóstico de PAF, atendidos no Ambulatório de Poliposes Intestinais do Departamento de Gastroenterologia do Hospital das Clínicas da Universidade de São Paulo. Os pacientes foram submetidos à duodenoscopia, classificados segundo Spigelman e a presença ou não de adenomas ampulares. Os pacientes foram distribuídos em dois grupos: Estadio de Spigelman de 0 a II, e Estadio III e IV. Estes grupos foram relacionados com variáveis clínicas, tais quais: sexo, idade, antecedentes familiares positivos de PAF, tipo de cirurgia do cólon, e tipo de polipose colônica. Naqueles pacientes classificados como Spigelman III e IV foi realizada enteroscopia assistida por balão via anterógrada para avaliação do jejuno. Resultados: Quarenta e nove pacientes foram classificados como estadios de Spigelman 0, I ou II, e 13 pacientes como estadios III ou IV. A análise da correlação destes grupos foi estatisticamente significativa com a variável história familiar (p = 0,03). Naquelas famílias que apresentaram vários parentes inclusos neste estudo, observou-se estadio de Spigelman similar entre os diferentes parentes de cada família. Sete pacientes apresentaram adenomas menores da papila duodenal. A associação da presença de adenoma de papila com a variável manifestações extraintestinais (p= 0,009) foi estatisticamente significante na análise multivariável. Enteroscopia assistida por balão foi realizada em 12 pacientes, dos quais 10 apresentaram adenomas tubulares com displasia de baixo grau no jejuno proximal. Conclusões: 1. A prevalência da adenomatose duodenal avançada e de adenomas ampulares é clinicamente significativa na PAF em nosso meio. 2. A prevalência de adenomas jejunais em pacientes com adenomatose duodenal avançada é alta, apesar de não serem lesões clinicamente significativas. No entanto, enteroscopia deve ser indicada de forma individualizada em casos de polipose duodenal avançada na avaliação da extensão do acometimento jejunal. 3. A intensidade da adenomatose duodenal pode ser previsível a partir da gravidade da adenomatose duodenal de algum parente de primeiro grau. 4. A presença de manifestações extracolônicas reforça a necessidade de avaliação da região da papila de Vater, desde que houve associação independente entre a presença de adenomas ampulares e as mesmas / Background: Patients with Familial Adenomatous Polyposis (FAP) have higher risk of duodenal cancer development compared with the general population. Spigelman classification has been adopted as the staging method of duodenal adenomatosis in patients with FAP. However, the relationship between the severity of duodenal polyposis and clinical variables is not well understood. Objectives: 1) To assess endoscopically, the prevalence and intensity of duodenojejunal adenomas in patients with FAP in our population. 2) To correlate clinical variables with the phenotypic severity of duodenal and ampullary adenomatosis. Methods: We prospectively studied 62 patients with FAP, attended at Intestinal polyposis Clinic of the Department of Gastroenterology, Clinics Hospital, University of São Paulo. Patients underwent duodenoscopy and were classified according to Spigelman and the presence or absence of ampullary adenomas. Patients were divided into two groups: Spigelman 0 to II and Stage III and IV. These groups were related to the clinical variables: gender, age, family history for FAP, type of colorectal surgery, and type of polyposis of the colon. Patients classified as Spigelman III and IV were submitted to balloon assisted enteroscopy for evaluation of the jejunum. Results: Forty-nine patients were staged as Spigelman 0, I or II, and 13 as stage III or IV. There was statistic significant correlation between these groups and family history (p = 0,03). Families that had several relatives included in this study showed that there was a similar Spigelman stage in different relatives of each family. Seven patients had minor ampullar adenomas. Association between ampullary adenomas and extraintestinal manifestations (p = 0.009) was statistically significant in multivariavel analysis. Balloon assisted enteroscopy was performed in 12 patients. Ten of those presented tubular adenomas with low grade dysplasia in the proximal jejunum. Conclusions: 1. The prevalence of advanced duodenal adenomatosis and ampullary adenomas is clinically significant in FAP patients of our population. 2. The prevalence of jejunal adenomas in patients with advanced duodenal adenomatosis is high, although lesions were not clinically significant. Indication for enteroscoDpy should be individualized in patients with advanced duodenal disease to evaluate jejunal disease. 3. The intensity of duodenal adenomatosis can be predicted upon the severity of duodenal polyposis of a first-degree relative. 4. The presence of extracolonic manifestations reinforces the importance for avaliation of the Vater Papilla since there was an independent association between ampullary adenomas and extracolonic manifestations

Introdução: Pacientes com Polipose Adenomatosa Familiar (PAF) tem maior risco de desenvolvimento de carcinoma duodenal em comparação com a população em geral, sendo a classificação de Spigelman adotada como método de estadiamento da adenomatose duodenal em doentes com PAF. No entanto, a relação entre a gravidade da polipose duodenal e variáveis clínicas não é bem compreendida. Objetivos: 1) Avaliar, através do método endoscópico, a prevalência e a intensidade da adenomatose duodenojejunal em pacientes com PAF em nosso meio. 2) Verificar a associação de variáveis clínicas, com a gravidade fenotípica da adenomatose duodenal e ampular. Metodologia: Foram estudados prospectivamente, 62 pacientes com diagnóstico de PAF, atendidos no Ambulatório de Poliposes Intestinais do Departamento de Gastroenterologia do Hospital das Clínicas da Universidade de São Paulo. Os pacientes foram submetidos à duodenoscopia, classificados segundo Spigelman e a presença ou não de adenomas ampulares. Os pacientes foram distribuídos em dois grupos: Estadio de Spigelman de 0 a II, e Estadio III e IV. Estes grupos foram relacionados com variáveis clínicas, tais quais: sexo, idade, antecedentes familiares positivos de PAF, tipo de cirurgia do cólon, e tipo de polipose colônica. Naqueles pacientes classificados como Spigelman III e IV foi realizada enteroscopia assistida por balão via anterógrada para avaliação do jejuno. Resultados: Quarenta e nove pacientes foram classificados como estadios de Spigelman 0, I ou II, e 13 pacientes como estadios III ou IV. A análise da correlação destes grupos foi estatisticamente significativa com a variável história familiar (p = 0,03). Naquelas famílias que apresentaram vários parentes inclusos neste estudo, observou-se estadio de Spigelman similar entre os diferentes parentes de cada família. Sete pacientes apresentaram adenomas menores da papila duodenal. A associação da presença de adenoma de papila com a variável manifestações extraintestinais (p= 0,009) foi estatisticamente significante na análise multivariável. Enteroscopia assistida por balão foi realizada em 12 pacientes, dos quais 10 apresentaram adenomas tubulares com displasia de baixo grau no jejuno proximal. Conclusões: 1. A prevalência da adenomatose duodenal avançada e de adenomas ampulares é clinicamente significativa na PAF em nosso meio. 2. A prevalência de adenomas jejunais em pacientes com adenomatose duodenal avançada é alta, apesar de não serem lesões clinicamente significativas. No entanto, enteroscopia deve ser indicada de forma individualizada em casos de polipose duodenal avançada na avaliação da extensão do acometimento jejunal. 3. A intensidade da adenomatose duodenal pode ser previsível a partir da gravidade da adenomatose duodenal de algum parente de primeiro grau. 4. A presença de manifestações extracolônicas reforça a necessidade de avaliação da região da papila de Vater, desde que houve associação independente entre a presença de adenomas ampulares e as mesmas / Background: Patients with Familial Adenomatous Polyposis (FAP) have higher risk of duodenal cancer development compared with the general population. Spigelman classification has been adopted as the staging method of duodenal adenomatosis in patients with FAP. However, the relationship between the severity of duodenal polyposis and clinical variables is not well understood. Objectives: 1) To assess endoscopically, the prevalence and intensity of duodenojejunal adenomas in patients with FAP in our population. 2) To correlate clinical variables with the phenotypic severity of duodenal and ampullary adenomatosis. Methods: We prospectively studied 62 patients with FAP, attended at Intestinal polyposis Clinic of the Department of Gastroenterology, Clinics Hospital, University of São Paulo. Patients underwent duodenoscopy and were classified according to Spigelman and the presence or absence of ampullary adenomas. Patients were divided into two groups: Spigelman 0 to II and Stage III and IV. These groups were related to the clinical variables: gender, age, family history for FAP, type of colorectal surgery, and type of polyposis of the colon. Patients classified as Spigelman III and IV were submitted to balloon assisted enteroscopy for evaluation of the jejunum. Results: Forty-nine patients were staged as Spigelman 0, I or II, and 13 as stage III or IV. There was statistic significant correlation between these groups and family history (p = 0,03). Families that had several relatives included in this study showed that there was a similar Spigelman stage in different relatives of each family. Seven patients had minor ampullar adenomas. Association between ampullary adenomas and extraintestinal manifestations (p = 0.009) was statistically significant in multivariavel analysis. Balloon assisted enteroscopy was performed in 12 patients. Ten of those presented tubular adenomas with low grade dysplasia in the proximal jejunum. Conclusions: 1. The prevalence of advanced duodenal adenomatosis and ampullary adenomas is clinically significant in FAP patients of our population. 2. The prevalence of jejunal adenomas in patients with advanced duodenal adenomatosis is high, although lesions were not clinically significant. Indication for enteroscoDpy should be individualized in patients with advanced duodenal disease to evaluate jejunal disease. 3. The intensity of duodenal adenomatosis can be predicted upon the severity of duodenal polyposis of a first-degree relative. 4. The presence of extracolonic manifestations reinforces the importance for avaliation of the Vater Papilla since there was an independent association between ampullary adenomas and extracolonic manifestations