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159 Publications visible to you, out of a total of 159
The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.
LIFE HNC - Head and Neck Cancer Group, Genetical Statistics and Systems Biology

Abstract (Expand)

Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We … characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.

Authors: G. Wichmann, M. Rosolowski, K. Krohn, M. Kreuz, A. Boehm, A. Reiche, U. Scharrer, D. Halama, J. Bertolini, U. Bauer, D. Holzinger, M. Pawlita, J. Hess, C. Engel, D. Hasenclever, M. Scholz, P. Ahnert, H. Kirsten, A. Hemprich, C. Wittekind, O. Herbarth, F. Horn, A. Dietz, M. Loeffler

Date Published: 15th Dec 2015

Publication Type: Not specified

Human Diseases: head and neck cancer

Incremental value of Veterans Specific Activity Questionnaire and the YMCA-step test for the assessment of cardiorespiratory fitness in population-based studies.
LIFE Heart

Abstract (Expand)

BACKGROUND: Cardiorespiratory fitness is a well-established independent predictor of cardiovascular health. However, the relevance of alternative exercise and non-exercise tests for cardiorespiratory … fitness assessment in large cohorts has not been studied in detail. We aimed to evaluate the YMCA-step test and the Veterans Specific Activity Questionnaire (VSAQ) for the estimation of cardiorespiratory fitness in the general population. METHODS: One hundred and five subjects answered the VSAQ, performed the YMCA-step test and a maximal cardiopulmonary exercise test (CPX) and gave BORG ratings for both exercise tests (BORGSTEP, BORGCPX). Correlations of peak oxygen uptake on a treadmill (VO2_PEAK) with VSAQ, BORGSTEP, one-minute, post-exercise heartbeat count, and peak oxygen uptake during the step test (VO2_STEP) were determined. Moreover, the incremental values of the questionnaire and the step test in addition to other fitness-related parameters were evaluated using block-wise hierarchical regression analysis. RESULTS: Eighty-six subjects completed the step test according to the protocol. For completers, correlations of VO2_PEAK with the age- and gender-adjusted VSAQ, heartbeat count and VO2_STEP were 0.67, 0.63 and 0.49, respectively. However, using hierarchical regression analysis, age, gender and body mass index already explained 68.8% of the variance of VO2_PEAK, while the additional benefit of VSAQ was rather low (3.4%). The inclusion of BORGSTEP, heartbeat count and VO2_STEP increased R(2) by a further 2.2%, 3.3% and 5.6%, respectively, yielding a total R(2) of 83.3%. CONCLUSIONS: Neither VSAQ nor the YMCA-step test contributes sufficiently to the assessment of cardiorespiratory fitness in population-based studies.

Authors: A. Teren, S. Zachariae, F. Beutner, R. Ubrich, M. Sandri, C. Engel, M. Loffler, S. Gielen

Date Published: 15th Dec 2015

Publication Type: Not specified

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

INTRODUCTION Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA …A alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers. METHODS We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals. RESULTS We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk. CONCLUSIONS This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Authors: Sophie Blein, Claire Bardel, Vincent Danjean, Lesley McGuffog, Sue Healey, Daniel Barrowdale, Andrew Lee, Joe Dennis, Karoline B. Kuchenbaecker, Penny Soucy, Mary Beth Terry, Wendy K. Chung, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Laima Tihomirova, Nadine Tung, Cecilia M. Dorfling, Elizabeth J. van Rensburg, Susan L. Neuhausen, Yuan Chun Ding, Anne-Marie Gerdes, Bent Ejlertsen, Finn C. Nielsen, Thomas vO Hansen, Ana Osorio, Javier Benitez, Raquel Andrés Conejero, Ena Segota, Jeffrey N. Weitzel, Margo Thelander, Paolo Peterlongo, Paolo Radice, Valeria Pensotti, Riccardo Dolcetti, Bernardo Bonanni, Bernard Peissel, Daniela Zaffaroni, Giulietta Scuvera, Siranoush Manoukian, Liliana Varesco, Gabriele L. Capone, Laura Papi, Laura Ottini, Drakoulis Yannoukakos, Irene Konstantopoulou, Judy Garber, Ute Hamann, Alan Donaldson, Angela Brady, Carole Brewer, Claire Foo, D. Gareth Evans, Debra Frost, Diana Eccles, Fiona Douglas, Jackie Cook, Julian Adlard, Julian Barwell, Lisa Walker, Louise Izatt, Lucy E. Side, M. John Kennedy, Marc Tischkowitz, Mark T. Rogers, Mary E. Porteous, Patrick J. Morrison, Radka Platte, Ros Eeles, Rosemarie Davidson, Shirley Hodgson, Trevor Cole, Andrew K. Godwin, Claudine Isaacs, Kathleen Claes, Kim de Leeneer, Alfons Meindl, Andrea Gehrig, Barbara Wappenschmidt, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Hansjoerg Plendl, Karin Kast, Kerstin Rhiem, Nina Ditsch, Norbert Arnold, Raymonda Varon-Mateeva, Rita K. Schmutzler, Sabine Preisler-Adams, Nadja Bogdanova Markov, Shan Wang-Gohrke, Antoine de Pauw, Cédrick Lefol, Christine Lasset, Dominique Leroux, Etienne Rouleau, Francesca Damiola, Hélène Dreyfus, Laure Barjhoux, Lisa Golmard, Nancy Uhrhammer, Valérie Bonadona, Valérie Sornin, Yves-Jean Bignon, Jonathan Carter, Linda van Le, Marion Piedmonte, Paul A. DiSilvestro, Miguel de La Hoya, Trinidad Caldes, Heli Nevanlinna, Kristiina Aittomäki, Agnes Jager, Ans Mw van den Ouweland, Carolien M. Kets, Cora M. Aalfs, Flora E. van Leeuwen, Frans Bl Hogervorst, Hanne Ej Meijers-Heijboer, Jan C. Oosterwijk, Kees Ep van Roozendaal, Matti A. Rookus, Peter Devilee, Rob B. van der Luijt, Edith Olah, Orland Diez, Alex Teulé, Conxi Lazaro, Ignacio Blanco, Jesús Del Valle, Anna Jakubowska, Grzegorz Sukiennicki, Jacek Gronwald, Jan Lubinski, Katarzyna Durda, Katarzyna Jaworska-Bieniek, Bjarni A. Agnarsson, Christine Maugard, Alberto Amadori, Marco Montagna, Manuel R. Teixeira, Amanda B. Spurdle, William Foulkes, Curtis Olswold, Noralane M. Lindor, Vernon S. Pankratz, Csilla I. Szabo, Anne Lincoln, Lauren Jacobs, Marina Corines, Mark Robson, Joseph Vijai, Andreas Berger, Anneliese Fink-Retter, Christian F. Singer, Christine Rappaport, Daphne Geschwantler Kaulich, Georg Pfeiler, Muy-Kheng Tea, Mark H. Greene, Phuong L. Mai, Gad Rennert, Evgeny N. Imyanitov, Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Sandrine Tchatchou, Amanda Ewart Toland, Inge Sokilde Pedersen, Mads Thomassen, Torben A. Kruse, Uffe Birk Jensen, Maria A. Caligo, Eitan Friedman, Jamal Zidan, Yael Laitman, Annika Lindblom, Beatrice Melin, Brita Arver, Niklas Loman, Richard Rosenquist, Olufunmilayo I. Olopade, Robert L. Nussbaum, Susan J. Ramus, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Banu K. Arun, Gillian Mitchell, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Dominique Stoppa-Lyonnet, Gilles Thomas, Jacques Simard, Fergus J. Couch, Kenneth Offit, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Sylvie Mazoyer, Catherine M. Phelan, Olga M. Sinilnikova, David G. Cox

Date Published: 1st Dec 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Eating Behaviour in the General Population: An Analysis of the Factor Structure of the German Version of the Three-Factor-Eating-Questionnaire (TFEQ) and Its Association with the Body Mass Index.
LIFE Adult

Abstract (Expand)

The Three-Factor-Eating-Questionnaire (TFEQ) is an established instrument to assess eating behaviour. Analysis of the TFEQ-factor structure was based on selected, convenient and clinical samples so … far. Aims of this study were (I) to analyse the factor structure of the German version of the TFEQ and (II)--based on the refined factor structure--to examine the association between eating behaviour and the body mass index (BMI) in a general population sample of 3,144 middle-aged and older participants (40-79 years) of the ongoing population based cohort study of the Leipzig Research Center for Civilization Diseases (LIFE Health Study). The factor structure was examined in a split-half analysis with both explorative and confirmatory factor analysis. Associations between TFEQ-scores and BMI values were tested with multiple regression analyses controlled for age, gender, and education. We found a three factor solution for the TFEQ with an 'uncontrolled eating', a 'cognitive restraint' and an 'emotional eating' domain including 29 of the original 51 TFEQ-items. Scores of the 'uncontrolled eating domain' showed the strongest correlation with BMI values (partial r = 0.26). Subjects with scores above the median in both 'uncontrolled eating' and 'emotional eating' showed the highest BMI values (mean = 29.41 kg/m(2)), subjects with scores below the median in all three domains showed the lowest BMI values (mean = 25.68 kg/m(2); F = 72.074, p<0.001). Our findings suggest that the TFEQ is suitable to identify subjects with specific patterns of eating behaviour that are associated with higher BMI values. Such information may help health care professionals to develop and implement more tailored interventions for overweight and obese individuals.

Authors: A. Loffler, T. Luck, F. S. Then, C. Sikorski, P. Kovacs, Y. Bottcher, J. Breitfeld, A. Tonjes, A. Horstmann, M. Loffler, C. Engel, J. Thiery, A. Villringer, M. Stumvoll, S. G. Riedel-Heller

Date Published: 1st Aug 2015

Publication Type: Not specified

The LIFE-Adult-Study: objectives and design of a population-based cohort study with 10,000 deeply phenotyped adults in Germany.
LIFE Adult, Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: The LIFE-Adult-Study is a population-based cohort study, which has recently completed the baseline examination of 10,000 randomly selected participants from Leipzig, a major city with 550,000 … inhabitants in the east of Germany. It is the first study of this kind and size in an urban population in the eastern part of Germany. The study is conducted by the Leipzig Research Centre for Civilization Diseases (LIFE). Our objective is to investigate prevalences, early onset markers, genetic predispositions, and the role of lifestyle factors of major civilization diseases, with primary focus on metabolic and vascular diseases, heart function, cognitive impairment, brain function, depression, sleep disorders and vigilance dysregulation, retinal and optic nerve degeneration, and allergies. METHODS/DESIGN: The study covers a main age range from 40-79 years with particular deep phenotyping in elderly participants above the age of 60. The baseline examination was conducted from August 2011 to November 2014. All participants underwent an extensive core assessment programme (5-6 h) including structured interviews, questionnaires, physical examinations, and biospecimen collection. Participants over 60 underwent two additional assessment programmes (3-4 h each) on two separate visits including deeper cognitive testing, brain magnetic resonance imaging, diagnostic interviews for depression, and electroencephalography. DISCUSSION: The participation rate was 33 %. The assessment programme was accepted well and completely passed by almost all participants. Biomarker analyses have already been performed in all participants. Genotype, transcriptome and metabolome analyses have been conducted in subgroups. The first follow-up examination will commence in 2016.

Authors: M. Loeffler, C. Engel, P. Ahnert, D. Alfermann, K. Arelin, R. Baber, F. Beutner, H. Binder, E. Brahler, R. Burkhardt, U. Ceglarek, C. Enzenbach, M. Fuchs, H. Glaesmer, F. Girlich, A. Hagendorff, M. Hantzsch, U. Hegerl, S. Henger, T. Hensch, A. Hinz, V. Holzendorf, D. Husser, A. Kersting, A. Kiel, T. Kirsten, J. Kratzsch, K. Krohn, T. Luck, S. Melzer, J. Netto, M. Nuchter, M. Raschpichler, F. G. Rauscher, S. G. Riedel-Heller, C. Sander, M. Scholz, P. Schonknecht, M. L. Schroeter, J. C. Simon, R. Speer, J. Staker, R. Stein, Y. Stobel-Richter, M. Stumvoll, A. Tarnok, A. Teren, D. Teupser, F. S. Then, A. Tonjes, R. Treudler, A. Villringer, A. Weissgerber, P. Wiedemann, S. Zachariae, K. Wirkner, J. Thiery

Date Published: 22nd Jul 2015

Publication Type: Not specified

Human Diseases: disease of mental health, mental depression, vascular disease, allergic hypersensitivity disease, sleep disorder, retinal degeneration

Polymorphisms in a Putative Enhancer at the 10q21.2 Breast Cancer Risk Locus Regulate NRBF2 Expression
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine … mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5’ of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer.

Authors: Hatef Darabi, Karen McCue, Jonathan Beesley, Kyriaki Michailidou, Silje Nord, Siddhartha Kar, Keith Humphreys, Deborah Thompson, Maya Ghoussaini, Manjeet K. Bolla, Joe Dennis, Qin Wang, Sander Canisius, Christopher G. Scott, Carmel Apicella, John L. Hopper, Melissa C. Southey, Jennifer Stone, Annegien Broeks, Marjanka K. Schmidt, Rodney J. Scott, Artitaya Lophatananon, Kenneth Muir, Matthias W. Beckmann, Arif B. Ekici, Peter A. Fasching, Katharina Heusinger, Isabel Dos-Santos-Silva, Julian Peto, Ian Tomlinson, Elinor J. Sawyer, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E. Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L. Neuhausen, Volker Arndt, Hermann Brenner, Christoph Engel, Alfons Meindl, Rita K. Schmutzler, Norbert Arnold, Hiltrud Brauch, Ute Hamann, Jenny Chang-Claude, Sofia Khan, Heli Nevanlinna, Hidemi Ito, Keitaro Matsuo, Natalia V. Bogdanova, Thilo Dörk, Annika Lindblom, Sara Margolin, Veli-Matti Kosma, Arto Mannermaa, Chiu-Chen Tseng, Anna H. Wu, Giuseppe Floris, Diether Lambrechts, Anja Rudolph, Paolo Peterlongo, Paolo Radice, Fergus J. Couch, Celine Vachon, Graham G. Giles, Catriona McLean, Roger L. Milne, Pierre-Antoine Dugué, Christopher A. Haiman, Gertraud Maskarinec, Christy Woolcott, Brian E. Henderson, Mark S. Goldberg, Jacques Simard, Soo H. Teo, Shivaani Mariapun, Åslaug Helland, Vilde Haakensen, Wei Zheng, Alicia Beeghly-Fadiel, Rulla Tamimi, Arja Jukkola-Vuorinen, Robert Winqvist, Irene L. Andrulis, Julia A. Knight, Peter Devilee, Robert A. E. M. Tollenaar, Jonine Figueroa, Montserrat García-Closas, Kamila Czene, Maartje J. Hooning, Madeleine Tilanus-Linthorst, Jingmei Li, Yu-Tang Gao, Xiao-Ou Shu, Angela Cox, Simon S. Cross, Robert Luben, Kay-Tee Khaw, Ji-Yeob Choi, Daehee Kang, Mikael Hartman, Wei Yen Lim, Maria Kabisch, Diana Torres, Anna Jakubowska, Jan Lubinski, James McKay, Suleeporn Sangrajrang, Amanda E. Toland, Drakoulis Yannoukakos, Chen-Yang Shen, Jyh-Cherng Yu, Argyrios Ziogas, Minouk J. Schoemaker, Anthony Swerdlow, Anne-Lise Borresen-Dale, Vessela Kristensen, Juliet D. French, Stacey L. Edwards, Alison M. Dunning, Douglas F. Easton, Per Hall, Georgia Chenevix-Trench

Date Published: 1st Jul 2015

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Activating ERBB2/HER2 mutations indicate susceptibility to pan-HER inhibitors in Lynch and Lynch-like colorectal cancer.
GC-HNPCC - German Consortium for Hereditary Non-Polyposis Colorectal Cancer

Abstract (Expand)

OBJECTIVE: Microsatellite instability (MSI) is detected in approximately 15% of all colorectal cancers (CRC) and virtually in all cases with Lynch syndrome. The MSI phenotype is caused by dysfunctional … mismatch repair (MMR) and leads to accumulation of DNA replication errors. Sporadic MSI CRC often harbours BRAF(V600E); however, no consistent data exist regarding targeted treatment approaches in BRAF(wt) MSI CRC. DESIGN: Mutations and quantitative MSI were analysed by deep sequencing in 196 formalin fixed paraffin embedded (FFPE) specimens comprising Lynch and Lynch-like CRCs from the German Hereditary Nonpolyposis Colorectal Cancer registry. Functional relevance of recurrent ERBB2/HER2 mutations was investigated in CRC cell lines using reversible and irreversible HER-targeting inhibitors, EGFR-directed antibody cetuximab, HER2-directed antibody trastuzumab and siRNA-mediated ERBB2/HER2 knockdown. RESULTS: Quantification of nucleotide loss in non-coding mononucleotide repeats distinguished microsatellite status with very high accuracy (area under curve=0.9998) and demonstrated progressive losses with deeper invasion of MMR-deficient colorectal neoplasms (p=0.008). Characterisation of BRAF(wt) MSI CRC revealed hot-spot mutations in well-known oncogenic drivers, including KRAS (38.7%), PIK3CA (36.5%), and ERBB2 (15.0%). L755S and V842I substitutions in ERBB2 were highly recurrent. Functional analyses in ERBB2-mutated MSI CRC cell lines revealed a differential response to HER-targeting compounds and superiority of irreversible pan-HER inhibitors. CONCLUSIONS: We developed a high-throughput deep sequencing approach for concomitant MSI and mutational analyses in FFPE specimens. We provided novel insights into clinically relevant alterations in MSI CRC and a rationale for targeting ERBB2/HER2 mutations in Lynch and Lynch-like CRC.

Authors: M. Kloth, V. Ruesseler, C. Engel, K. Koenig, M. Peifer, E. Mariotti, H. Kuenstlinger, A. Florin, U. Rommerscheidt-Fuss, U. Koitzsch, C. Wodtke, F. Ueckeroth, S. Holzapfel, S. Aretz, P. Propping, M. Loeffler, S. Merkelbach-Bruse, M. Odenthal, N. Friedrichs, L. C. Heukamp, T. Zander, R. Buettner

Date Published: 24th May 2015

Publication Type: Not specified

Human Diseases: colorectal cancer

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