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Z Gastroenterol ; 57(11): 1309-1320, 2019 Nov.
Artículo en Alemán | MEDLINE | ID: mdl-31739377


INTRODUCTION: Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15-46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. METHODS: The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. RESULTS: A surveillance colonoscopy should be performed every 12-24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2-13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4-8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12-36 months starting by the age of 25 years. CONCLUSION: LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed.

Neoplasias Colorrectales Hereditarias sin Poliposis/patología , Reparación de la Incompatibilidad de ADN , Endoscopía del Sistema Digestivo/métodos , Guías de Práctica Clínica como Asunto , Conducta de Reducción del Riesgo , Neoplasias Colorrectales , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Alemania , Humanos , Vigilancia de la Población , Factores de Tiempo
Hum Mutat ; 40(5): 649-655, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30740824


Constitutional mismatch repair deficiency (CMMRD) is caused by germline pathogenic variants in both alleles of a mismatch repair gene. Patients have an exceptionally high risk of numerous pediatric malignancies and benefit from surveillance and adjusted treatment. The diversity of its manifestation, and ambiguous genotyping results, particularly from PMS2, can complicate diagnosis and preclude timely patient management. Assessment of low-level microsatellite instability in nonneoplastic tissues can detect CMMRD, but current techniques are laborious or of limited sensitivity. Here, we present a simple, scalable CMMRD diagnostic assay. It uses sequencing and molecular barcodes to detect low-frequency microsatellite variants in peripheral blood leukocytes and classifies samples using variant frequencies. We tested 30 samples from 26 genetically-confirmed CMMRD patients, and samples from 94 controls and 40 Lynch syndrome patients. All samples were correctly classified, except one from a CMMRD patient recovering from aplasia. However, additional samples from this same patient tested positive for CMMRD. The assay also confirmed CMMRD in six suspected patients. The assay is suitable for both rapid CMMRD diagnosis within clinical decision windows and scalable screening of at-risk populations. Its deployment will improve patient care, and better define the prevalence and phenotype of this likely underreported cancer syndrome.

Cell Mol Life Sci ; 69(22): 3863-79, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22760497


CD24 is a glycosyl-phosphatidylinositol-anchored membrane protein that is frequently over-expressed in a variety of human carcinomas and is correlated with poor prognosis. In cancer cell lines, changes of CD24 expression can alter several cellular properties in vitro and tumor growth in vivo. However, little is known about how CD24 mediates these effects. Here we have analyzed the functional consequences of CD24 knock-down or over-expression in human cancer cell lines. Depletion of CD24 reduced cell proliferation and adhesion, enhanced apoptosis, and regulated the expression of various genes some of which were identified as STAT3 target genes. Loss of CD24 reduced STAT3 and FAK phosphorylation. Diminished STAT3 activity was confirmed by specific reporter assays. We found that reduced STAT3 activity after CD24 knock-down was accompanied by altered Src phosphorylation. Silencing of Src, similar to CD24, targeted the expression of prototype STAT3-regulated genes. Likewise, the over-expression of CD24 augmented Src-Y416 phosphorylation, the recruitment of Src into lipid rafts and the expression of STAT3-dependent target genes. An antibody to CD24 was effective in reducing tumor growth of A549 lung cancer and BxPC3 pancreatic cancer xenografts in mice. Antibody treatment affected the level of Src-phosphorylation in the tumor and altered the expression of STAT3 target genes. Our results provide evidence that CD24 regulates STAT3 and FAK activity and suggest an important role of Src in this process. Finally, the targeting of CD24 by antibodies could represent a novel route for tumor therapy.

Antígeno CD24/metabolismo , Adhesión Celular/genética , Quinasa 1 de Adhesión Focal/metabolismo , Neoplasias/metabolismo , Factor de Transcripción STAT3/metabolismo , Familia-src Quinasas/metabolismo , Animales , Anticuerpos Monoclonales , Apoptosis/genética , Antígeno CD24/genética , Antígeno CD24/inmunología , Línea Celular Tumoral , Proliferación Celular , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Trasplante de Neoplasias , Fosforilación , Interferencia de ARN , ARN Interferente Pequeño , Trasplante Heterólogo , Familia-src Quinasas/genética