Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.586
Filtrar
1.
Surg Clin North Am ; 100(3): 483-498, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32402295

RESUMO

For most individuals, cancer development is multifactorial; however, up to 10% of all cancers are related to an inherited genetic mutation. As health care shifts to having a greater emphasis on prevention, care providers, including general surgeons, will need to play a role in identifying patients at high risk for cancer development. Genetic testing provides a tool to determine those patients with a genetic mutation and to whom appropriate preventive care and treatment may be offered. It is imperative for general surgeons to understand the role genetics plays in the care of individual patients and their relatives.


Assuntos
Neoplasias/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Mutacional de DNA , Feminino , Aconselhamento Genético , Testes Genéticos , Humanos , Masculino , Neoplasias/diagnóstico , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Linhagem , Cuidado Pré-Concepcional , Medição de Risco , Neoplasias Gástricas/genética
2.
Bull Cancer ; 107(5): 586-600, 2020 May.
Artigo em Francês | MEDLINE | ID: mdl-32362383

RESUMO

MUTYH-associated polyposis (MUTYH-associated polyposis, MAP) is an autosomal recessive inheritance disorder related to bi-allelic constitutional pathogenic variants of the MUTYH gene which was first described in 2002. In 2011, a group of French experts composed of clinicians and biologists, performed a summary of the available data on this condition and drew up recommendations concerning the indications and the modalities of molecular analysis of the MUTYH gene in index cases and their relatives, as well as the management of affected individuals. In view of recent developments, some recommendations have become obsolete, in particular with regard to the molecular analysis strategy since MUTYH gene has been recently included in a consensus panel of 14 genes predisposing to colorectal cancer. This led us to revise all the points of the previous expertise. We report here the revised version of this work which successively considers the phenotype and the tumor risks associated with this genotype, the differential diagnoses, the indication criteria and the strategy of the molecular analysis and the recommendations for the management of affected individuals. We also discuss the phenotype and the tumor risks associated with mono-allelic pathogenic variants of MUTYH gene.


Assuntos
Polipose Adenomatosa do Colo/genética , DNA Glicosilases/genética , Polipose Adenomatosa do Colo/diagnóstico , Polipose Adenomatosa do Colo/terapia , Alelos , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , DNA Glicosilases/análise , Diagnóstico Diferencial , Neoplasias do Sistema Digestório/genética , Saúde da Família , França , Predisposição Genética para Doença , Humanos , Neoplasias/genética , Fenótipo
3.
Medicine (Baltimore) ; 99(16): e19828, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32312003

RESUMO

BACKGROUND: The methylation status of the adenomatous polyposis coli (APC) promoter has been shown to be associated with the occurrence of gastric cancer, but this finding remains controversial. The aim of this study was to investigate the relationship between methylation of the APC gene promoter and gastric cancer. METHODS: We searched the Web of Science, EMBASE, Medline, and Cochrane Central Register of Controlled Trials (CENTRAL) databases from the date of creation until August 1, 2019. According to the inclusion criteria, the relationship between the methylation status of the APC gene promoter and gastric cancer was investigated. The incidence of APC promoter methylation in the tissues or blood of patients with and without gastric cancer was compared. The results are expressed as the odds ratio (OR) and 95% confidence interval (CI). The pooled OR of each study was estimated using a fixed effects model or a random effects model to generate forest plots. We further validated the results using the MethHC database. RESULTS: Eight studies (985 samples) were included. Our meta-analysis showed that the incidence of APC promoter methylation in patients with gastric cancer was higher than that of patients without gastric cancer (OR = 3.86, 95% CI 1.71-8.74, P = .001). Methylation of the APC promoter is associated with the incidence of gastric cancer, and it increases the risk of gastric cancer. CONCLUSION: This study provides a new strategic direction for research on gastric cancer. Methylation of the APC promoter may be a potential biomarker for the diagnosis of gastric cancer, but the results of this work require further confirmation.


Assuntos
Biologia Computacional/métodos , Metilação de DNA/genética , Genes APC/fisiologia , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Polipose Adenomatosa do Colo/genética , Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Humanos , Incidência , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/mortalidade
6.
Cancer Sci ; 111(4): 1367-1374, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31991021

RESUMO

Colorectal cancer (CRC) is the second leading cause of cancer death worldwide. Therefore, it is important to establish useful methods for preventing CRC. One prevention strategy involves the use of cancer chemopreventive agents, including functional foods. We focused on the well-known cancer chemopreventive agent curcumin, which is derived from turmeric. However, curcumin has the disadvantage of being poorly soluble in water due to its high hydrophobicity. To overcome this problem, the formation of submicron particles with surface controlled technology has been applied to curcumin to give it remarkably improved water solubility, and this derived compound is named Theracurmin. To date, the preventive effects of Theracurmin on hereditary intestinal carcinogenesis have not been elucidated. Thus, we used Apc-mutant mice, a model of familial adenomatous polyposis, to evaluate the effects of Theracurmin. First, we showed that treatment with 10-20 µM Theracurmin for 24 hours reduced nuclear factor-κB (NF-κB) transcriptional activity in human colon cancer DLD-1 and HCT116 cells. However, treatment with curcumin mixed in water did not change the NF-κB promoter transcriptional activity. As NF-κB is a regulator of inflammation-related factors, we next investigated the downstream targets of NF-κB: monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-6. We found that treatment with 500 ppm Theracurmin for 8 weeks inhibited intestinal polyp development and suppressed MCP-1 and IL-6 mRNA expression levels in the parts of the intestine with polyps. This report provides a proof of concept for the ongoing Theracurmin human trial (J-CAP-C study).


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Quimiocina CCL2/genética , Neoplasias Colorretais/tratamento farmacológico , Curcumina/farmacologia , Interleucina-6/genética , Polipose Adenomatosa do Colo/tratamento farmacológico , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Carcinogênese/efeitos dos fármacos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Curcumina/análogos & derivados , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HCT116 , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/patologia , Pólipos Intestinais/tratamento farmacológico , Pólipos Intestinais/genética , Pólipos Intestinais/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Camundongos , NF-kappa B/genética
7.
Dis Colon Rectum ; 63(2): 183-189, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31914111

RESUMO

BACKGROUND: Researchers are searching in vain for a coherent genetic explanation for serrated polyposis. We hypothesize that there is no consistent monogenetic inheritance. OBJECTIVE: The purpose of this study was to describe the serrated polyposis phenotype, assessing features of mendelian inheritance, and to compare these features with patients with a solitary sessile serrated lesion. DESIGN: This was a retrospective review of a prospectively maintained database comparing patients with serrated polyposis versus solitary sessile serrated lesions. SETTINGS: The study was conducted at a single-institution tertiary referral center. PATIENTS: Patients with serrated polyposis meeting World Health Organization criteria type I (≥5 serrated polyps proximal to the sigmoid, ≥2 of which are ≥10 mm in diameter) and isolated sessile serrated lesions were included MAIN OUTCOME MEASURES:: Disease phenotype was the main outcome measured. RESULTS: A total of 46 serrated polyposis patients were identified. Median age of first sessile serrated lesion was 66 years (interquartile range, 42-70 y). A total of 60.3% were current or past smokers (mean = 38.6 packs per year). Serrated polyposis patients had a higher number of all types of polyps (26.3 vs 4.4) and a higher rate of high-grade dysplasia (19.6% vs 3.7%) compared with patients with a solitary sessile serrated lesion. A total of 36.2% of patients had personal history of noncolorectal cancers, including skin, prostate, breast, thyroid, and renal cell cancers and leukemia. In addition, 32.6% had a family history of colorectal cancer in first- or second-degree relatives; these cancers were not young age of onset. Breast and prostate cancers were also common (family history of any cancer, 83.0%). Ten patients underwent genetic testing: 4 had negative panels, 1 had a pathogenic variant in MSH2, 1 an IVS7 deletion in PTEN, 2 negative APC sequencing (1 negative MYH), and 1 a pathogenic variant in Chek2. LIMITATIONS: RNF4 was not sequenced. Genetic analysis was performed on a subset of patients. CONCLUSIONS: The rate of associated cancers suggests an underlying genetic predisposition to disordered growth, but serrated polyposis does not have typical features of dominant inheritance. The association with smoking suggests that familial/environmental factors play a role. See Video Abstract at http://links.lww.com/DCR/B84. POLIPOSIS SERRADA SÉSIL: ¿NO ES UN SÍNDROME HEREDITARIO?: Los investigadores están buscando en vano una explicación genética coherente para la póliposis serrados. Suponemos que no existe una herencia monogenética consistente.1) Describir el fenotipo de póliposis serrada, evaluando las características de la herencia mendeliana, 2) comparar estas características con pacientes con una lesión serrada sésil solitaria.Revisión retrospectiva de una base de datos mantenida prospectivamente que compara pacientes con póliposis serrada versus lesiones serradas sésiles solitarias.Institución única, centro de referencia terciario.Pacientes con póliposis serrada que cumplen con los Criterios de la Organización Mundial de la Salud Tipo I (≥ 5 pólipos serrados proximales al sigmoideo, ≥2 de los cuales tienen ≥10 mm de diámetro) y lesiones serradas sésiles aisladas.Fenotipo de la enfermedad.Se identificaron un total de 46 pacientes con póliposis serrada. La edad mediana de la primera lesión serrada sésil fue de 66 años (RIC: 42-70 años). El 60.3% eran fumadores actuales o pasados (medio 38.6 paquetes / año). Los pacientes con póliposis serrada tuvieron un mayor número de todos los tipos de pólipos (26.3 versus 4.4) y una mayor tasa de displasia de alto grado (19.6% versus 3.7%) en comparación con los pacientes con una lesión serrada sésil solitaria. El 36.2% de los pacientes tenían antecedentes personales de cánceres no colorectales, incluyendo los cánceres de piel, próstata, mama, tiroides, células renales y leucemia. El 32.6% tenía antecedentes familiares de cáncer colorectal en familiares de primer o segundo grado; estos cánceres no eran de inicio de edad temprana. El cáncer de mama y próstata también fue frecuente (antecedentes familiares de cualquier tipo de cáncer: 83.0%). 10 pacientes se sometieron a pruebas genéticas: 4 tenían paneles negativos, 1 tenía una variante patogénica en MSH2, 1 una eliminación IVS7 en PTEN, 2 secuenciación APC negativa (1 MYH negativa) y 1 variante patogénica en Chek2.RNF4 no fue secuenciado. El análisis genético se realizó en un subconjunto de pacientes.La tasa de cánceres asociados sugiere una predisposición genética subyacente al crecimiento desordenado, pero la póliposis serrada no tiene características típicas de herencia dominante. La asociación con el tabaquismo sugiere que los factores familiares / ambientales juegan un papel. Consulte Video Resumen en http://links.lww.com/DCR/B84. (Traducción-Dr. Yesenia Rojas-Khalil).


Assuntos
Polipose Adenomatosa do Colo/genética , Testes Genéticos/métodos , Anamnese/estatística & dados numéricos , Polipose Adenomatosa do Colo/diagnóstico por imagem , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Endoscopia Gastrointestinal/métodos , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/genética , Estudos Retrospectivos , Fumar/efeitos adversos
8.
Bull Cancer ; 107(3): 346-351, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31955867

RESUMO

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of ß-catenin plays a major role. A mutation of the CTNNB1 encoding ß-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of ß-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.


Assuntos
Fibromatose Agressiva/etiologia , Transdução de Sinais/fisiologia , Polipose Adenomatosa do Colo/genética , Carcinogênese , Elafina/metabolismo , Estrogênios/metabolismo , Fibromatose Agressiva/genética , Fibromatose Agressiva/metabolismo , Fibromatose Agressiva/patologia , Genes APC , Proteínas Hedgehog/metabolismo , Humanos , Janus Quinases/metabolismo , Linfotoxina-alfa/metabolismo , Metaloproteases/metabolismo , Mutação , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Notch/metabolismo , Fatores de Transcrição STAT/metabolismo , Serina-Treonina Quinases TOR/metabolismo , beta Catenina/genética
9.
Bull Cancer ; 107(3): 364-370, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31812283

RESUMO

After an adapted imaging, the diagnosis of a desmoid tumor (DT) is provided by a percutaneous microbiopsy, with a molecular analysis for beta-catenin or APC gene mutation. The therapeutic strategy must be decided in a specialized multidisciplinary tumor board (MTB). Surgery is no longer the first-line treatment for a DT. Except within a surgical complication, active surveillance is offered to the majority of patients, since more than half stabilize or regress after an initial progression, whether the location is peripheral or intra-abdominal. If the localization and/or volume are likely to be functional or life-threatening, medical induction therapy is discussed in MTB, before a local treatment whose potential sequelae would be definitive. Incomplete unplanned resection, recurrence, pregnancy or desmoids occurring in a polyposis context are no longer routine surgical indications. In an emergency setting (occlusion, peritonitis), it is discussed to treat only the mechanical complication and leave the DT in place, if its resection would lead to too much digestive resection, especially in patients who have already undergone colectomy for polyposis. The best indications for surgery are patients who have parietal locations with significant and documented progression, because surgery can be easily completed at the cost of an acceptable morbidity. In localizations where surgery would cause sequelae, medical treatment or other regional loco treatments are discussed in MTB.


Assuntos
Fibromatose Agressiva/cirurgia , Polipose Adenomatosa do Colo/cirurgia , Biópsia/métodos , Progressão da Doença , Feminino , Fibromatose Agressiva/complicações , Fibromatose Agressiva/patologia , Genes APC , Humanos , Obstrução Intestinal/terapia , Recidiva Local de Neoplasia , Regressão Neoplásica Espontânea , Peritonite/terapia , Complicações Pós-Operatórias/cirurgia , Gravidez , Complicações Neoplásicas na Gravidez/cirurgia , Indução de Remissão , Carga Tumoral , Conduta Expectante
10.
Int J Cancer ; 146(4): 1064-1074, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31283021

RESUMO

As a large number of cancers are caused by nonsense mutations in key genes, read-through of these mutations to restore full-length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read-through as a potential chemo-preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read-through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor-suppressing activity. Together, our findings show that induced read-through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/tratamento farmacológico , Eritromicina/administração & dosagem , Transcrição Genética/efeitos dos fármacos , Polipose Adenomatosa do Colo/diagnóstico por imagem , Polipose Adenomatosa do Colo/genética , Administração Oral , Adolescente , Adulto , Idoso , Criança , Códon sem Sentido , Códon de Terminação/genética , Colonoscopia , Eritromicina/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Pediatr Blood Cancer ; 67(3): e28110, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31802619

RESUMO

BACKGROUND: APC gene pathogenic variants are characterized by a lifetime risk of nearly 100% to develop a colorectal carcinoma. International guidelines suggest a prophylactic surgery in the second decade. METHODS: A descriptive analysis was performed evaluating a surgical series of adolescent patients with familial adenomatous polyposis (FAP) enrolled in the prospectively maintained hereditary polyposis registry. RESULTS: Thirty-eight adolescent patients (median age 16 years; range, 7-19) underwent laparoscopic prophylactic surgery. APC gene pathogenic variants were detected in all patients, and six patients were proband. No patients were converted to open surgery. Median postoperative stay was five days (4-16). Early postoperative complications were one dural puncture and one anastomotic leakage. Regarding late complications, we observed one patient having small bowel obstruction 56 months after surgery. Pathological reports showed one patient with pTis adenocarcinoma in two separate sites; 33 patients with low-grade dysplasia, four with high-grade dysplasia. One patient developed a desmoid tumor 37 months after surgery. After a median follow-up of 40.5 months, no patients died or had a second abdominal surgery because of cancer in rectal stump. CONCLUSIONS: Rectal sparing surgery was the first choice in the major respect of patients' quality of life. Laparoscopic prophylactic surgery for FAP is well accepted from adolescents. It represents a safe option due to the low incidence of post-surgical desmoids and quick postoperative recovery.


Assuntos
Adenocarcinoma/cirurgia , Polipose Adenomatosa do Colo/cirurgia , Laparoscopia/métodos , Complicações Pós-Operatórias , Qualidade de Vida , Adenocarcinoma/patologia , Polipose Adenomatosa do Colo/patologia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
12.
Gut ; 69(3): 411-444, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31780574

RESUMO

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Vigilância da População , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/prevenção & controle , Polipose Adenomatosa do Colo/terapia , Colonoscopia , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/genética , Neoplasias Colorretais Hereditárias sem Polipose/prevenção & controle , Neoplasias Colorretais Hereditárias sem Polipose/terapia , DNA Glicosilases/genética , Saúde da Família , Humanos , Polipose Intestinal/congênito , Polipose Intestinal/genética , Polipose Intestinal/terapia , Irlanda , Estilo de Vida , Síndromes Neoplásicas Hereditárias/genética , Síndromes Neoplásicas Hereditárias/terapia , Síndrome de Peutz-Jeghers/genética , Síndrome de Peutz-Jeghers/terapia , Encaminhamento e Consulta/normas , Fatores de Risco , Reino Unido
13.
Proc Natl Acad Sci U S A ; 117(2): 857-864, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31882448

RESUMO

Cancer is driven by the sequential accumulation of genetic and epigenetic changes in oncogenes and tumor suppressor genes. The timing of these events is not well understood. Moreover, it is currently unknown why the same driver gene change appears as an early event in some cancer types and as a later event, or not at all, in others. These questions have become even more topical with the recent progress brought by genome-wide sequencing studies of cancer. Focusing on mutational events, we provide a mathematical model of the full process of tumor evolution that includes different types of fitness advantages for driver genes and carrying-capacity considerations. The model is able to recapitulate a substantial proportion of the observed cancer incidence in several cancer types (colorectal, pancreatic, and leukemia) and inherited conditions (Lynch and familial adenomatous polyposis), by changing only 2 tissue-specific parameters: the number of stem cells in a tissue and its cell division frequency. The model sheds light on the evolutionary dynamics of cancer by suggesting a generalized early onset of tumorigenesis followed by slow mutational waves, in contrast to previous conclusions. Formulas and estimates are provided for the fitness increases induced by driver mutations, often much larger than previously described, and highly tissue dependent. Our results suggest a mechanistic explanation for why the selective fitness advantage introduced by specific driver genes is tissue dependent.


Assuntos
Carcinogênese/genética , Modelos Genéticos , Neoplasias/classificação , Polipose Adenomatosa do Colo/genética , Idoso , Divisão Celular , Neoplasias Colorretais/genética , Neoplasias Colorretais Hereditárias sem Polipose , Humanos , Pessoa de Meia-Idade , Mutação , Neoplasias/genética , Oncogenes/genética
14.
Gut ; 69(1): 112-121, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30981990

RESUMO

BACKGROUND AND AIMS: Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1-2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies. METHODS: Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance. RESULTS: We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p<0.001). Most patients were recommended a 2-year interval, and those recommended a 2-year interval were not at increased risk of AN: AN incidence after a 2-year recommendation was 15.6% compared with 24.4% after a 1-year recommendation (OR 0.57, p=0.08). CONCLUSION: Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance. TRIAL REGISTRATION NUMBER: The study was registered on http://www.trialregister.nl; trial-ID NTR4609.


Assuntos
Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Polipose Adenomatosa do Colo/epidemiologia , Polipose Adenomatosa do Colo/cirurgia , Idoso , Estudos de Coortes , Colonoscopia/métodos , Colonoscopia/estatística & dados numéricos , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/cirurgia , Feminino , Seguimentos , Humanos , Incidência , Masculino , Sobremedicalização/prevenção & controle , Sobremedicalização/estatística & dados numéricos , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Vigilância da População/métodos , Prevalência , Estudos Prospectivos , Fatores de Risco , Espanha/epidemiologia
16.
Bull Cancer ; 107(3): 352-358, 2020 Mar.
Artigo em Francês | MEDLINE | ID: mdl-31882269

RESUMO

About 15 % of patients with familial adenomatous polyposis "PAF" develop one or more desmoid tumors in their lifetime. These are benign mesenchymal tumors with local aggressivity but with no potential for metastases. Most of the desmoids tumors result from a sporadic genetic anomaly in the ß catenin gene. When related to familial adenomatous polyposis or "PAF", this mutation is not present, and the patients must be sent in genetic counselling. The PAF is a dominant autosomic illness related to a germinal mutation in the APC gene. Sometimes, these tumors can be the first manifestation of the illness. The diagnosis in a context of PAF can be easily done by imaging, but a pathological confirmation is needed. These tumors raise a therapeutic problem because of their heterogeneity and the absence of predictive biomarkers along illness evolution. The identification of prognostic biological and clinical factors would make easier the selection of patients requiring first-line treatment, as spontaneous remissions have also been observed in patients with FAP whom which an active surveillance could also be a valid therapeutic option. The particularity of desmoids tumors associated to PAF lies in their predominantly intra-abdominal location and the risk of complication. In the last ten years, surgery has largely given way to conservative treatments such as chemotherapy and more recently to tyrosine kinase inhibitors that have shown their efficacy with a significant improvement in progression-free survival of patients.


Assuntos
Fibromatose Agressiva/genética , Síndrome de Gardner/genética , Neoplasias Abdominais/diagnóstico , Neoplasias Abdominais/genética , Neoplasias Abdominais/terapia , Parede Abdominal , Polipose Adenomatosa do Colo/genética , Feminino , Fibromatose Agressiva/diagnóstico , Fibromatose Agressiva/terapia , Síndrome de Gardner/diagnóstico , Síndrome de Gardner/terapia , Genes APC , Humanos , Masculino , Seleção de Pacientes , Gravidez , Complicações Neoplásicas na Gravidez/etiologia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Conduta Expectante
17.
Biomed Pharmacother ; 121: 109572, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704613

RESUMO

Colorectal Cancer (CRC) is highly heterogeneous for which prognosis is dependent mainly on clinical staging. There is a need to stratify subpopulations of CRC on molecular basis to better predict outcome and therapy response. Truncating mutations in adenomatous polyposis coli (APC) are well-described events in CRC carcinogenesis. Clinical and genotypic characterization of Middle Eastern CRC based on presence and type of APC was determined in 412 CRC tumors using modern next generation sequencing. APC truncating mutations were identified in 58.2% (240/412) of CRCs. Overall, mutation was significant predictor of superior overall survival. Further, the type of APC mutations (short or long) did not have impact on clinical outcome. However, in vitro analysis showed difference between CRC cell lines carrying short truncating APC vs CRC cells that carry long truncating APC mutation in response to 5-flourouracil (5-FU). Importantly, we were able to overcome the resistance to 5-FU seen in CRC cells carrying short APC by tankyrase inhibitor, XAV939, thereby inhibiting Wnt/ß-catenin signaling cascade. Overall, our results showed that APC mutation status plays an important role in predicting overall survival in Middle Eastern population. Furthermore, in vitro data showed that selective targeting of APC mutated CRC by tankyrase inhibitor can be an effective strategy to overcome 5-FU resistance in CRC cells.


Assuntos
Polipose Adenomatosa do Colo/genética , Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/farmacologia , Idoso , Linhagem Celular Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Arábia Saudita , Sobrevida , Tanquirases/antagonistas & inibidores , Tanquirases/metabolismo , Via de Sinalização Wnt/genética
18.
Biomed Pharmacother ; 121: 109534, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810128

RESUMO

The ApcMin/+ mouse is an animal model for familial adenomatous polyposis, and aged ApcMin/+ mice also spontaneously develop multiple tumors in their stomachs. However, gastric premalignant lesions in ApcMin/+ mice have not been well characterized. The stomachs of ApcMin/+ mice were compared with those of their wild type littermates at 24 weeks with hematoxylin and eosin (H&E) staining and alcian blue staining. Ki67, CD68 and CA199 expression was analyzed by immunohistochemistry. The results revealed the presence of epithelial proliferation and inflammatory infiltration in the forestomachs, glandular atrophy and intestinal metaplasia in the gastric bodies, and dysplasia in the gastric antra. The effect of mutations in the Apc gene on chronic gastritis and gastric precancerous lesions was characterized in ApcMin/+ mice. These results suggest that ApcMin/+ mice represent a genetic model for mechanistic studies and drug discovery in gastric precancerous lesions.


Assuntos
Polipose Adenomatosa do Colo/genética , Lesões Pré-Cancerosas/patologia , Estômago/patologia , Animais , Dissecação , Feminino , Mucosa Gástrica/patologia , Antígeno Ki-67/metabolismo , Masculino , Camundongos Endogâmicos C57BL
19.
Bratisl Lek Listy ; 120(12): 908-911, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31855049

RESUMO

Familial adenomatous polyposis (FAP) is an inherited autosomal dominant disorder. Extracolonic manifestations are seen quite often. As prophylactic colectomy has become a standard care in FAP patients, the concerns over the development of associated extracolonic malignancies have become more prevalent. The authors report a case of a patient with the history of subtotal colectomy because of FAP with the development of adenocarcinoma of papilla of Vater twenty-six years later. A radical procedure in form of proximal pancreaticoduodenectomy was indicated. Variable endoscopic surveillance protocols and treatment strategies have been proposed concerning the management of duodenal and periampullary lesions. In case of periampullary malignancies, the radical surgical resection offers the only chance for cure and the only option that may safeguard the long­term survival (Fig. 2, Ref. 30). Keywords: ampulla of Vater, bile duct, obstructive jaundice, pancreatoduodenectomy, periampullary tumors.


Assuntos
Ampola Hepatopancreática/diagnóstico por imagem , Ampola Hepatopancreática/cirurgia , Colectomia/efeitos adversos , Colectomia/métodos , Neoplasias do Colo/cirurgia , Neoplasias do Ducto Colédoco/cirurgia , Pancreaticoduodenectomia/métodos , Polipose Adenomatosa do Colo/complicações , Ampola Hepatopancreática/patologia , Colangiopancreatografia Retrógrada Endoscópica , Neoplasias do Colo/complicações , Neoplasias do Ducto Colédoco/complicações , Neoplasias do Ducto Colédoco/patologia , Neoplasias Duodenais , Humanos , Icterícia Obstrutiva/etiologia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
20.
BMJ Case Rep ; 12(11)2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31712236

RESUMO

Familial adenomatous polyposis (FAP) is an autosomal dominant syndrome associated with mutation in the adenomatous polyposis coli (APC) gene, a tumour suppressor located on chromosome 5q21. Attenuated familial adenomatous polyposis (AFAP) is a variant associated with fewer and later onset of colon polyps. AFAP-associated APC mutations have largely been found before codon 157, in exon 9 or after codon 1595. We present the case of a 44-year-old man incidentally found to have numerous gastric polyps during bariatric surgery, with innumerable polyps in the remaining part of the stomach and the entire colon, with rectal sparing, consistent with AFAP phenotype. Genetic testing demonstrated the c.7682dup (p.Ser2562Lysfs*21) variant in exon 15 of APC. This represents a previously undescribed APC mutation. This mutation likely yields end-binding protein 1 and human disc large binding protein inactivation, causing cell cycle microtubule dysregulation and tumour suppressor inactivation. Through loss of these regulatory mechanisms, this mutation is associated with AFAP phenotype. The patient was treated surgically and is doing well.


Assuntos
Polipose Adenomatosa do Colo/genética , Proteínas dos Microfilamentos/genética , Mutação/genética , Polipose Adenomatosa do Colo/cirurgia , Adulto , Colectomia/métodos , Humanos , Masculino , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA