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Spier I.,University of Bonn | Drichel D.,German Center for Neurodegenerative Diseases | Kerick M.,Max Planck Institute for Molecular Genetics | Kerick M.,University of Cologne | And 21 more authors.
Journal of Medical Genetics | Year: 2016

Background In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreadingassociated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis. Methods To comprehensively screen for somatic lowlevel APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods. Results In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene. Conclusions The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.


Spier I.,University of Bonn | Holzapfel S.,University of Bonn | Altmuller J.,University of Cologne | Zhao B.,Howard Hughes Medical Institute | And 17 more authors.
International Journal of Cancer | Year: 2015

In a number of families with colorectal adenomatous polyposis or suspected Lynch syndrome/HNPCC, no germline alteration in the APC, MUTYH, or mismatch repair (MMR) genes are found. Missense mutations in the polymerase genes POLE and POLD1 have recently been identified as rare cause of multiple colorectal adenomas and carcinomas, a condition termed polymerase proofreading-associated polyposis (PPAP). The aim of the present study was to evaluate the clinical relevance and phenotypic spectrum of polymerase germline mutations. Therefore, targeted sequencing of the polymerase genes POLD1, POLD2, POLD3, POLD4, POLE, POLE2, POLE3 and POLE4 was performed in 266 unrelated patients with polyposis or fulfilled Amsterdam criteria. The POLE mutation c.1270C>G;p.Leu424Val was detected in four unrelated patients. The mutation was present in 1.5% (4/266) of all patients, 4% (3/77) of all familial cases and 7% (2/30) of familial polyposis cases. The colorectal phenotype in 14 affected individuals ranged from typical adenomatous polyposis to a HNPCC phenotype, with high intrafamilial variability. Multiple colorectal carcinomas and duodenal adenomas were common, and one case of duodenal carcinoma was reported. Additionally, various extraintestinal lesions were evident. Nine further putative pathogenic variants were identified. The most promising was c.1306C>T;p.Pro436Ser in POLE. In conclusion, a PPAP was identified in a substantial number of polyposis and familial colorectal cancer patients. Screening for polymerase proofreading mutations should therefore be considered, particularly in unexplained familial cases. The present study broadens the phenotypic spectrum of PPAP to duodenal adenomas and carcinomas, and identified novel, potentially pathogenic variants in four polymerase genes. © 2014 UICC.


van Boxel O.S.,University Utrecht | ter Linde J.J.M.,University Utrecht | Oors J.,University Utrecht | Otto B.,Medizinische Klinik Campus Innenstadt | And 3 more authors.
Neurogastroenterology and Motility | Year: 2012

Background Duodenal lipid intensifies the perception of esophageal acid perfusion. Recently, we showed that genes implicated in lipid absorption were upregulated in the duodenum of fasting gastro-esophageal reflux disease (GERD) patients. This suggests that chylomicron production and secretion may be enhanced and, consequently, the release of apolipoprotein A-IV (apoA-IV), a chylomicron-derived signaling protein. ApoA-IV may stimulate release of cholecystokinin (CCK), an activator of vagal afferents. This study evaluated putative involvement of abnormal apoA-IV and CCK responses to lipid in GERD. Methods Ten GERD patients and 10 healthy volunteers (HV) underwent duodenal perfusion with Intralipid 20%, 2kcal min -1, for 60min. Symptoms were scored, blood samples collected every 15min during lipid perfusion and 15min after discontinuation when duodenal biopsies were taken. Plasma and mucosal concentrations of apoA-IV and CCK and transcript levels of 21 genes implicated in lipid absorption, differentially expressed under fasting conditions, were quantified. Key Results Heartburn (P=0.003), abdominal discomfort (P=0.037) and nausea (P= 0.008) only increased significantly during lipid infusion in GERD patients. Following lipid infusion mean mucosal apoA-IV concentration was lower in GERD patients compared with HV (P=0.023), whereas plasma concentration tended to be elevated (P=0.068). Mean mucosal CCK concentration was also lower in GERD patients (P=0.009). Two genes, HIBADH and JTB, were upregulated in GERD patients (P=0.008 and P=0.038, respectively). Conclusions & Inferences Our results suggest excessive duodenal lipid-induced release of apoA-IV and CCK in GERD. We postulate that the resulting heightened activation of duodenal vagal afferents may underlie central sensitization, thereby increasing the perception of reflux events. © 2012 Blackwell Publishing Ltd.


Peter F.,Buda Childrens Hospital | Bidlingmaier M.,Medizinische Klinik Campus Innenstadt | Savoy C.,Biopartners GmbH | Ji H.-J.,LG Life science Ltd. | Saenger P.H.,Yeshiva University
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Background: GH treatment currently requires daily sc injections, resulting in suboptimal compliance. A GH regimen with fewer injections may offer patients and caregivers a less arduous option. LB03002 is a novel sustained-release GH formulation for once-weekly dosing. Patients and Methods: GH-deficient, GH-naive prepubertal children were randomized to four groups who received 0.2 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); 0.5 mg/kg/wk LB03002 for 36 months (n=13); 0.7 mg/kg/wk LB03002 for 12 months, followed by 0.5 mg/kg/wk for another 24 months (n=13); or daily GH 0.03 mg/kg/d for 24 months, switched to 0.5 mg/kg/wk LB03002 for 12 months (n = 12). Results: Height velocity increased in all groups; the increase was less for the 0.2 mg/kg/wk LB03002 group at 12 (P = 0.008) and 24 months (P = 0.030), with no statistically significant differences at any time for the 0.5 mg/kg/wk and 0.7 mg/kg/wk LB03002 groups, vs. daily GH. Height SD score gain at 12 months was significantly (P = 0.023) less for the 0.2 mg/kg/wk group (1.05 ± 0.38) than daily GH (1.47 ± 0.29), but with no statistically significant difference for the 0.5 mg/kg/wk (1.37 ± 0.39) and 0.7 mg/kg/wk (1.50±0.44) LB03002 groups vs. daily GH. There were no significant differences in height SD score gain between any groups at 24 and 36 months. Bone maturation did not differ for any LB03002 dose compared with daily GH. Serum IGF-I concentrations increased as expected, with no long-term differences between groups. Mean fasting glucose and glycosylated hemoglobin concentrations did not exceed normal ranges for any treatment group at any time. Conclusion: LB03002 at doses of 0.5 mg/kg/wk and 0.7 mg/kg/wk was shown to be effective and safe with once-weekly dosing in GH-deficient children, and 0.5 mg/kg/wk LB03002 was chosen as the optimal dose for long-term assessment. Copyright © 2012 by The Endocrine Society.


Yang R.,German Cancer Research Center | Yang R.,University of Heidelberg | Chen B.,German Cancer Research Center | Pfutze K.,German Cancer Research Center | And 27 more authors.
Carcinogenesis | Year: 2014

Colorectal cancer (CRC) is one of the most common cancer worldwide. However, a large number of genetic risk factors involved in CRC have not been understood. Copy number variations (CNVs) might partly contribute to the 'missing heritability' of CRC. An increased overall burden of CNV has been identified in several complex diseases, whereas the association between the overall CNV burden and CRC risk is largely unknown. We performed a genome-wide investigation of CNVs on genomic DNA from 384 familial CRC cases and 1285 healthy controls by the Affymetrix 6.0 array. An increase of overall CNV burden was observed in familial CRC patients compared with healthy controls, especially for CNVs larger than 50 kb (case/control ratio = 1.66, P = 0.025). In addition, we discovered for the first time a novel structural variation at 12p12.3 and determined the breakpoints by strategic PCR and sequencing. This 12p12.3 structural variation was found in four of 2862 CRC cases but not in 6243 healthy controls (P = 0.0098). RERGL gene (RERG/RAS-like), the only gene influenced by the 12p12.3 structural variation, sharing most of the conserved regions with its close family member RERG tumor suppressor gene (RAS-like, estrogen-regulated, growth inhibitor), might be a novel CRC-related gene. In conclusion, this is the first study to reveal the contribution of the overall burden of CNVs to familial CRC risk and identify a novel rare structural variation at 12p12.3 containing RERGL gene to be associated with CRC. © The Author 2013. Published by Oxford University Press. All rights reserved.


Dimopoulou C.,Medizinische Klinik Campus Innenstadt | Dimopoulou C.,Max Planck Institute of Psychiatry | Ormanns S.,Ludwig Maximilians University of Munich | Eigenbrod S.,Ludwig Maximilians University of Munich | And 3 more authors.
Experimental and Clinical Endocrinology and Diabetes | Year: 2012

Introduction: A plasmocytoma involving the pituitary gland is an extremely rare entity, with approximately 22 cases of solitary myeloma or multiple myeloma presenting with sellar mass reported in the literature so far. Case report: Here, we report the case of a 71-year-old female patient affected by an extramedullary IgG-lambda multiple myeloma presenting as a pituitary mass lesion. We summarize the diagnostic approaches that confirmed the diagnosis of multiple myeloma and describe treatment outcome after therapy. Discussion: Intrasellar plasmocytoma though rare, should be considered in the differential diagnosis of a pituitary mass lesion, since associated with different therapeutic and prognostic implications. Physicians should be alert for intrasellar plasma cell tumors in case of well preserved anterior pituitary function in combination with cranial nerve neuropathies and sellar destruction. © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart - New York.


Lippl F.,Medizinische Klinik Campus Innenstadt | Erdmann J.,TU Munich | Steiger A.,Medizinische Klinik Campus Innenstadt | Lichter N.,Medizinische Klinik Campus Innenstadt | And 4 more authors.
Regulatory Peptides | Year: 2012

Ghrelin is the only peripheral orexigenic peptide of gastrointestinal origin. Its preprandial increase is supposed to initiate food intake. This assumption is based on studies with intravenously infused ghrelin in rather high doses and the correlation between ghrelin levels and hunger sensations. As yet it is unclear whether or not low dose ghrelin resulting in physiological and moderately supraphysiological plasma levels has an effect on hunger sensations, the wish for food intake and / or the quantity of the meal consumed.We examined 20 normal-weight males (age 25±1.7years, BMI 24±0.5kg/m 2) in a prospective double-blind randomized fashion. On two different days they obtained a ghrelin infusion 1ng/kg/min or intravenous saline starting one hour after a standardized meal. Hunger and satiety ratings were documented by visual analogue scales. A second meal was served on demand and consumed until feeling satiated. Time point of the second meal as well as ingested calories were registered.Prior to the start of i.v. ghrelin the postprandial decrease of active plasma ghrelin by 30. pg/ml was comparable. In the controls the postprandial reduction was significant until 210. min compared to basal. With i.v. ghrelin basal levels were reached within 10. min. The maximal rise was twice basal. No effect was observed on hunger and satiety ratings. The time period between the meals and the food quantity of the second meal were similar. During ghrelin infusion glucose and growth hormone but not insulin and cortisol levels were significantly higher after the second meal compared to saline.The present data demonstrate for the first time the effect of a low dose ghrelin infusion on food intake. Neither physiological nor moderably supraphysiological ghrelin levels were associated with any change of the various food intake parameters determined. These data do not favour a hormonal role of peripheral ghrelin in the regulation of food intake. © 2011 Elsevier B.V.

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