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159 Publications visible to you, out of a total of 159
A breast cancer risk haplotype in the caspase-8 gene
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has … been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.

Authors: Neil Duncan Shephard, Ryan Abo, Sushila Harkisandas Rigas, Bernd Frank, Wei-Yu Lin, Ian Wallace Brock, Adam Shippen, Sabapathy Prakash Balasubramanian, Malcolm Walter Ronald Reed, Claus Rainer Bartram, Alfons Meindl, Rita Katharina Schmutzler, Christoph Engel, Barbara Burwinkel, Lisa Anne Cannon-Albright, Kristina Allen-Brady, Nicola Jane Camp, Angela Cox

Date Published: 24th Mar 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers … in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2.

Authors: A. Osorio, M. Pollán, G. Pita, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Arnold, S. Preisler-Adams, D. Niederacher, W. Hofmann, D. Gadzicki, A. Jakubowska, U. Hamann, J. Lubinski, A. Toloczko-Grabarek, C. Cybulski, T. Debniak, G. Llort, D. Yannoukakos, O. Díez, B. Peissel, P. Peterlongo, P. Radice, T. Heikkinen, H. Nevanlinna, P. L. Mai, J. T. Loud, L. McGuffog, A. C. Antoniou, J. Benitez

Date Published: 1st Sep 2008

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common breast cancer-predisposition alleles are associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A … recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p(trend) = 1.7 x 10(-8) and HR = 1.12, 95% CI: 1.02-1.24, p(trend) = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p(trend) = 5 x 10(-5) in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Authors: Antonis C. Antoniou, Amanda B. Spurdle, Olga M. Sinilnikova, Sue Healey, Karen A. Pooley, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Wera Hofmann, Christian Sutter, Dieter Niederacher, Helmut Deissler, Trinidad Caldes, Kati Kämpjärvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A. Ganz, Mary B. Daly, Gail Tomlinson, Olufunmilayo I. Olopade, Joanne L. Blum, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H. Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne-Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Gemma Llort, Roger L. Milne, Javier Benítez, Ute Hamann, Frans B. L. Hogervorst, Peggy Manders, Marjolijn J. L. Ligtenberg, Ans M. W. van den Ouweland, Susan Peock, Margaret Cook, Radka Platte, D. Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas, Andrew K. Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M. Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 1st Apr 2008

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
SepNet - German Competence Network Sepsis

Abstract (Expand)

BACKGROUND: The role of intensive insulin therapy in patients with severe sepsis is uncertain. Fluid resuscitation improves survival among patients with septic shock, but evidence is lacking to support … the choice of either crystalloids or colloids. METHODS: In a multicenter, two-by-two factorial trial, we randomly assigned patients with severe sepsis to receive either intensive insulin therapy to maintain euglycemia or conventional insulin therapy and either 10% pentastarch, a low-molecular-weight hydroxyethyl starch (HES 200/0.5), or modified Ringer's lactate for fluid resuscitation. The rate of death at 28 days and the mean score for organ failure were coprimary end points. RESULTS: The trial was stopped early for safety reasons. Among 537 patients who could be evaluated, the mean morning blood glucose level was lower in the intensive-therapy group (112 mg per deciliter [6.2 mmol per liter]) than in the conventional-therapy group (151 mg per deciliter [8.4 mmol per liter], P<0.001). However, at 28 days, there was no significant difference between the two groups in the rate of death or the mean score for organ failure. The rate of severe hypoglycemia (glucose level, < or = 40 mg per deciliter [2.2 mmol per liter]) was higher in the intensive-therapy group than in the conventional-therapy group (17.0% vs. 4.1%, P<0.001), as was the rate of serious adverse events (10.9% vs. 5.2%, P=0.01). HES therapy was associated with higher rates of acute renal failure and renal-replacement therapy than was Ringer's lactate. CONCLUSIONS: The use of intensive insulin therapy placed critically ill patients with sepsis at increased risk for serious adverse events related to hypoglycemia. As used in this study, HES was harmful, and its toxicity increased with accumulating doses. (ClinicalTrials.gov number, NCT00135473.)

Authors: F. M. Brunkhorst, C. Engel, F. Bloos, A. Meier-Hellmann, M. Ragaller, N. Weiler, O. Moerer, M. Gruendling, M. Oppert, S. Grond, D. Olthoff, U. Jaschinski, S. John, R. Rossaint, T. Welte, M. Schaefer, P. Kern, E. Kuhnt, M. Kiehntopf, C. Hartog, C. Natanson, M. Loeffler, K. Reinhart

Date Published: 10th Jan 2008

Publication Type: Not specified

Human Diseases: bacterial infectious disease

Current practice in nutritional support and its association with mortality in septic patients–results from a national, prospective, multicenter study
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany. DESIGN Nationwide …ide prospective, observational, cross-sectional, 1-day point-prevalence study. SETTING The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size. PATIENTS Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29-3.37). CONCLUSIONS Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.

Authors: Gunnar Elke, Dirk Schädler, Christoph Engel, Holger Bogatsch, Inez Frerichs, Maximilian Ragaller, Jens Scholz, Frank M. Brunkhorst, Markus Löffler, Konrad Reinhart, Norbert Weiler

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

Practice and perception–a nationwide survey of therapy habits in sepsis
SepNet - German Competence Network Sepsis

Abstract (Expand)

OBJECTIVE To simultaneously determine perceived vs. practiced adherence to recommended interventions for the treatment of severe sepsis or septic shock. DESIGN One-day cross-sectional survey. SETTING …TING Representative sample of German intensive care units stratified by hospital size. PATIENTS Adult patients with severe sepsis or septic shock. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Practice recommendations were selected by German Sepsis Competence Network (SepNet) investigators. External intensivists visited intensive care units randomly chosen and asked the responsible intensive care unit director how often these recommendations were used. Responses \textquotedblalways\textquotedbl and \textquotedblfrequently\textquotedbl were combined to depict perceived adherence. Thereafter patient files were audited. Three hundred sixty-six patients on 214 intensive care units fulfilled the criteria and received full support. One hundred fifty-two patients had acute lung injury or acute respiratory distress syndrome. Low-tidal volume ventilation \textless or = 6 mL/kg/predicted body weight was documented in 2.6% of these patients. A total of 17.1% patients had tidal volume between 6 and 8 mL/kg predicted body weight and 80.3% \textgreater 8 mL/kg predicted body weight. Mean tidal volume was 10.0 +/- 2.4 mL/kg predicted body weight. Perceived adherence to low-tidal volume ventilation was 79.9%. Euglycemia (4.4-6.1 mmol/L) was documented in 6.2% of 355 patients. A total of 33.8% of patients had blood glucose levels \textless or = 8.3 mmol/L and 66.2% were hyperglycemic (blood glucose \textgreater 8.3 mmol/L). Among 207 patients receiving insulin therapy, 1.9% were euglycemic, 20.8% had blood glucose levels \textless or = 8.3 mmol/L, and 1.0% were hypoglycemic. Overall, mean maximal glucose level was 10.0 +/- 3.6 mmol/L. Perceived adherence to strict glycemic control was 65.9%. Although perceived adherence to recommendations was higher in academic and larger hospitals, actual practice was not significantly influenced by hospital size or university affiliation. CONCLUSIONS This representative survey shows that current therapy of severe sepsis in German intensive care units complies poorly with practice recommendations. Intensive care unit directors perceive adherence to be higher than it actually is. Implementation strategies involving all intensive care unit staff are needed to overcome this gap between current evidence-based knowledge, practice, and perception.

Authors: Frank M. Brunkhorst, Christoph Engel, Max Ragaller, Tobias Welte, Rolf Rossaint, Herwig Gerlach, Konstantin Mayer, Stefan John, Frank Stuber, Norbert Weiler, Michael Oppert, Onnen Moerer, Holger Bogatsch, Konrad Reinhart, Markus Loeffler, Christiane Hartog

Date Published: 2008

Publication Type: Journal article

Human Diseases: disease by infectious agent

RAD51 135G–C modifies breast cancer risk among BRCA2 mutation carriers: results from a combined analysis of 19 studies
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

RAD51 is an important component of double-stranded DNA-repair mechanisms that interacts with both BRCA1 and BRCA2. A single-nucleotide polymorphism (SNP) in the 5’ untranslated region (UTR) of RAD51, … 135G–\textgreaterC, has been suggested as a possible modifier of breast cancer risk in BRCA1 and BRCA2 mutation carriers. We pooled genotype data for 8,512 female mutation carriers from 19 studies for the RAD51 135G–\textgreaterC SNP. We found evidence of an increased breast cancer risk in CC homozygotes (hazard ratio [HR] 1.92 [95% confidence interval CI 1.25-2.94) but not in heterozygotes (HR 0.95 [95% CI 0.83-1.07]; P=.002, by heterogeneity test with 2 degrees of freedom [df]). When BRCA1 and BRCA2 mutation carriers were analyzed separately, the increased risk was statistically significant only among BRCA2 mutation carriers, in whom we observed HRs of 1.17 (95% CI 0.91-1.51) among heterozygotes and 3.18 (95% CI 1.39-7.27) among rare homozygotes (P=.0007, by heterogeneity test with 2 df). In addition, we determined that the 135G–\textgreaterC variant affects RAD51 splicing within the 5’ UTR. Thus, 135G–\textgreaterC may modify the risk of breast cancer in BRCA2 mutation carriers by altering the expression of RAD51. RAD51 is the first gene to be reliably identified as a modifier of risk among BRCA1/2 mutation carriers.

Authors: Antonis C. Antoniou, Olga M. Sinilnikova, Jacques Simard, Mélanie Léoné, Martine Dumont, Susan L. Neuhausen, Jeffery P. Struewing, Dominique Stoppa-Lyonnet, Laure Barjhoux, David J. Hughes, Isabelle Coupier, Muriel Belotti, Christine Lasset, Valérie Bonadona, Yves-Jean Bignon, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Susan M. Domchek, Katherine L. Nathanson, Judy E. Garber, Jeffrey Weitzel, Steven A. Narod, Gail Tomlinson, Olufunmilayo I. Olopade, Andrew Godwin, Claudine Isaacs, Anna Jakubowska, Jan Lubinski, Jacek Gronwald, Bohdan Górski, Tomasz Byrski, Tomasz Huzarski, Susan Peock, Margaret Cook, Caroline Baynes, Alexandra Murray, Mark Rogers, Peter A. Daly, Huw Dorkins, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Amanda B. Spurdle, Xiaoqing Chen, Nicola Waddell, Nicole Cloonan, Tomas Kirchhoff, Kenneth Offit, Eitan Friedman, Bella Kaufmann, Yael Laitman, Gilli Galore, Gad Rennert, Flavio Lejbkowicz, Leon Raskin, Irene L. Andrulis, Eduard Ilyushik, Hilmi Ozcelik, Peter Devilee, Maaike P. G. Vreeswijk, Mark H. Greene, Sheila A. Prindiville, Ana Osorio, Javier Benitez, Michal Zikan, Csilla I. Szabo, Outi Kilpivaara, Heli Nevanlinna, Ute Hamann, Francine Durocher, Adalgeir Arason, Fergus J. Couch, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 1st Dec 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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