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1005 Publications visible to you, out of a total of 1005
Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in the BRCA1 gene substantially increase a woman’s lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers … identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Authors: David G. Cox, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, Sue Healey, Csilla Szabo, Mark H. Greene, Phuong L. Mai, Irene L. Andrulis, Mads Thomassen, Anne-Marie Gerdes, Maria A. Caligo, Eitan Friedman, Yael Laitman, Bella Kaufman, Shani S. Paluch, Åke Borg, Per Karlsson, Marie Stenmark Askmalm, Gisela Barbany Bustinza, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Javier Benítez, Ute Hamann, Matti A. Rookus, Ans M. W. van den Ouweland, Margreet G. E. M. Ausems, Cora M. Aalfs, Christi J. van Asperen, Peter Devilee, Hans J. J. P. Gille, Susan Peock, Debra Frost, D. Gareth Evans, Ros Eeles, Louise Izatt, Julian Adlard, Joan Paterson, Jacqueline Eason, Andrew K. Godwin, Marie-Alice Remon, Virginie Moncoutier, Marion Gauthier-Villars, Christine Lasset, Sophie Giraud, Agnès Hardouin, Pascaline Berthet, Hagay Sobol, François Eisinger, Brigitte Bressac de Paillerets, Olivier Caron, Capucine Delnatte, David Goldgar, Alex Miron, Hilmi Ozcelik, Saundra Buys, Melissa C. Southey, Mary Beth Terry, Christian F. Singer, Anne-Catharina Dressler, Muy-Kheng Tea, Thomas v. O. Hansen, Oskar Johannsson, Marion Piedmonte, Gustavo C. Rodriguez, Jack B. Basil, Stephanie Blank, Amanda E. Toland, Marco Montagna, Claudine Isaacs, Ignacio Blanco, Simon A. Gayther, Kirsten B. Moysich, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Christian Sutter, Dorothea Gadzicki, Britta Fiebig, Trinidad Caldes, Rachel Laframboise, Heli Nevanlinna, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Paolo Peterlongo, Siranoush Manoukian, Loris Bernard, Paolo Radice, Douglas F. Easton, Georgia Chenevix-Trench, Antonis C. Antoniou, Dominique Stoppa-Lyonnet, Sylvie Mazoyer, Olga M. Sinilnikova

Date Published: 1st Dec 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Comparison of scoring methods for the detection of causal genes with or without rare variants
Genetical Statistics and Systems Biology

Abstract (Expand)

Rare causal variants are believed to significantly contribute to the genetic basis of common diseases or quantitative traits. Appropriate statistical methods are required to discover the highest possible … number of disease-relevant variants in a genome-wide screening study. The publicly available Genetic Analysis Workshop 17 data set consists of 697 individuals and 24,487 genetic variants. It includes a simulated complex disease model with intermediate quantitative phenotypes. We compare four gene-wise scoring methods with respect to ranking of causal genes under variable allele frequency thresholds for collapsing of rare variants and considering whether or not rare variants were included. We also compare causal genes for which the ranks differ clearly between scoring methods regarding such characteristics as number and strength of causal variants. We corroborated our findings with additional simulations. We found that the maximum statistics method was superior in assigning high ranks to genes with a single strong causal variant. Hotelling’s T2 test was superior for genes with several independent causal variants. This was consistent for all phenotypes and was confirmed by single-gene analyses and additional simulations. The multivariate analysis performed similarly to Hotelling’s T2 test. The least absolute shrinkage and selection operator (LASSO) analysis was widely comparable with the maximum statistics method. We conclude that the maximum statistics method is a superior alternative to Hotelling’s T2 test if one expects only one independent causal variant per gene with a dominating effect. Such a variant could also be a supermarker derived by collapsing rare variants. Because the true nature of the genetic effect is unknown for real data, both methods need to be taken into consideration.

Authors: Markus Scholz, Holger Kirsten

Date Published: 1st Dec 2011

Publication Type: Journal article

CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: To describe incidence, risk factors, and influence of treatment on occurrence of central nervous system (CNS) relapse or progression in younger patients with aggressive B-cell lymphoma. … PATIENTS AND METHODS: We analyzed 2210 patients with aggressive B-cell lymphoma treated on various studies for CNS relapse/progression. Treatment consisted of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) +/- etoposide. Six hundred and twenty patients also received rituximab. CNS prophylaxis was intrathecal methotrexate on High-CHOEP and MegaCHOEP phase III studies if upper neck, head, bone marrow, or testes were involved. RESULTS: Fifty-six of 2196 patients (2.6%) developed CNS disease. It occurred early (median 7.0 months), median survival was 5.0 months. Patients with age-adjusted International Prognostic Index (aaIPI) 0 or 1 treated with rituximab showed a low risk for CNS disease (2-year rates: 0% or 0.5%), and rituximab decreased the risk (relative risk 0.3, 95% confidence interval 0.1-0.9, P = 0.029). Patients with aaIPI 2 or 3 showed a moderate risk (4.2%-9.7%) and no significant reduction of CNS disease with rituximab. CNS prophylaxis was of no significant benefit. CONCLUSIONS: In younger patients with aaIPI 0 or 1, CNS relapse/progression is very rare; in patients with aaIPI 2 or 3, the risk is higher (up to 10%) and requires new diagnostic strategies and treatment.

Authors: N. Schmitz, S. Zeynalova, B. Glass, U. Kaiser, E. Cavallin-Stahl, M. Wolf, M. Haenel, M. Loeffler, L. Truemper, M. Pfreundschuh

Date Published: 13th Oct 2011

Publication Type: Not specified

Human Diseases: B-cell lymphoma

High resolution genomic profiling and classical cytogenetics in a group of benign and atypical meningiomas
Genetical Statistics and Systems Biology

Abstract (Expand)

Meningiomas are classified as benign, atypical, or anaplastic. The majority are sporadic, solitary, and benign tumors with favorable prognoses. However, the prognosis for patients with anaplastic … meningiomas remains less favorable. High resolution genomic profiling has the capacity to provide more detailed information. Therefore, we analyzed genomic aberrations of benign and atypical meningiomas using single nucleotide polymorphism (SNP) array, combined with G-banding by trypsin using Giemsa stain (GTG banding), spectral karyotyping, and locus-specific fluorescence in situ hybridization (FISH). We confirmed frequently detected chromosomal aberrations in meningiomas and identified novel genetic events. Applying SNP array, we identified constitutional de novo loss or gain within chromosome 22 in three patients, possibly representing inherited causal events for meningioma formation. We show evidence for somatic segmental uniparental disomy in regions 4p16.1, 7q31.2, 8p23.2, and 9p22.1 not previously described for primary meningioma. GTG-banding and spectral karyotyping detected a novel balanced reciprocal translocation t(4;10)(q12;q26) in one benign meningioma. A paracentric inversion within 1p36, previously described as novel, was detected as a recurrent chromosomal aberration in benign and atypical meningiomas. Analyses of tumors and matched normal tissues with a combination of SNP arrays and complementary techniques will help to further elucidate potentially causal genetic events for tumorigenesis of meningioma.

Authors: Heidrun Holland, Kristin Mocker, Peter Ahnert, Holger Kirsten, Helene Hantmann, Ronald Koschny, Manfred Bauer, Ralf Schober, Markus Scholz, Jürgen Meixensberger, Wolfgang Krupp

Date Published: 1st Oct 2011

Publication Type: Journal article

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.
GLA - German Lymphoma Alliance, MMML Demonstrators - Molecular Mechanisms in Malignant Lymphomas - Demonstrators of Personalized Medicine

Abstract (Expand)

BACKGROUND: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young … patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. METHODS: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. FINDINGS: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0.03-119), 6-year event-free survival was 55.8% (95% CI 50.4-60.9; 166 events) for patients assigned to chemotherapy alone and 74.3% (69.3-78.6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18.5%, 11.5-25.4, log-rank p<0.0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84.3% [95% CI 74.2-90.7] vs 71.0% [65.1-76.1], log-rank p=0.005). 18 (4.4%, 95% CI 2.6-6.9) second malignancies occurred in the chemotherapy-alone group and 16 (3.9%, 2.2-6.2) in the chemotherapy and rituximab group (Fisher's exact p=0.730). INTERPRETATION: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. FUNDING: Hoffmann-La Roche.

Authors: M. Pfreundschuh, E. Kuhnt, L. Trumper, A. Osterborg, M. Trneny, L. Shepherd, D. S. Gill, J. Walewski, R. Pettengell, U. Jaeger, P. L. Zinzani, O. Shpilberg, S. Kvaloy, P. de Nully Brown, R. Stahel, N. Milpied, A. Lopez-Guillermo, V. Poeschel, S. Grass, M. Loeffler, N. Murawski

Date Published: 24th Sep 2011

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

Genetic variation in the Sorbs of eastern Germany in the context of broader European genetic diversity
Genetical Statistics and Systems Biology

Abstract (Expand)

Population isolates have long been of interest to genetic epidemiologists because of their potential to increase power to detect disease-causing genetic variants. The Sorbs of Germany are considered … as cultural and linguistic isolates and have recently been the focus of disease association mapping efforts. They are thought to have settled in their present location in eastern Germany after a westward migration from a largely Slavic-speaking territory during the Middle Ages. To examine Sorbian genetic diversity within the context of other European populations, we analyzed genotype data for over 30 000 autosomal single-nucleotide polymorphisms from over 200 Sorbs individuals. We compare the Sorbs with other European individuals, including samples from population isolates. Despite their geographical proximity to German speakers, the Sorbs showed greatest genetic similarity to Polish and Czech individuals, consistent with the linguistic proximity of Sorbian to other West Slavic languages. The Sorbs also showed evidence of subtle levels of genetic isolation in comparison with samples from non-isolated European populations. The level of genetic isolation was less than that observed for the Sardinians and French Basque, who were clear outliers on multiple measures of isolation. The finding of the Sorbs as only a minor genetic isolate demonstrates the need to genetically characterize putative population isolates, as they possess a wide range of levels of isolation because of their different demographic histories.

Authors: Krishna R. Veeramah, Anke Tönjes, Peter Kovacs, Arnd Gross, Daniel Wegmann, Patrick Geary, Daniela Gasperikova, Iwar Klimes, Markus Scholz, John Novembre, Michael Stumvoll

Date Published: 1st Sep 2011

Publication Type: Journal article

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide … association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r(2) = 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 \times 10(-9) for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 \times 10(-8) for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

Authors: Antonis C. Antoniou, Christiana Kartsonaki, Olga M. Sinilnikova, Penny Soucy, Lesley McGuffog, Sue Healey, Andrew Lee, Paolo Peterlongo, Siranoush Manoukian, Bernard Peissel, Daniela Zaffaroni, Elisa Cattaneo, Monica Barile, Valeria Pensotti, Barbara Pasini, Riccardo Dolcetti, Giuseppe Giannini, Anna Laura Putignano, Liliana Varesco, Paolo Radice, Phuong L. Mai, Mark H. Greene, Irene L. Andrulis, Gord Glendon, Hilmi Ozcelik, Mads Thomassen, Anne-Marie Gerdes, Torben A. Kruse, Uffe Birk Jensen, Dorthe G. Crüger, Maria A. Caligo, Yael Laitman, Roni Milgrom, Bella Kaufman, Shani Paluch-Shimon, Eitan Friedman, Niklas Loman, Katja Harbst, Annika Lindblom, Brita Arver, Hans Ehrencrona, Beatrice Melin, Katherine L. Nathanson, Susan M. Domchek, Timothy Rebbeck, Ania Jakubowska, Jan Lubinski, Jacek Gronwald, Tomasz Huzarski, Tomasz Byrski, Cezary Cybulski, Bohdan Gorski, Ana Osorio, Teresa Ramón y Cajal, Florentia Fostira, Raquel Andrés, Javier Benitez, Ute Hamann, Frans B. Hogervorst, Matti A. Rookus, Maartje J. Hooning, Marcel R. Nelen, Rob B. van der Luijt, Theo A. M. van Os, Christi J. van Asperen, Peter Devilee, Hanne E. J. Meijers-Heijboer, Encarna B. Gómez Garcia, Susan Peock, Margaret Cook, Debra Frost, Radka Platte, Jean Leyland, D. Gareth Evans, Fiona Lalloo, Ros Eeles, Louise Izatt, Julian Adlard, Rosemarie Davidson, Diana Eccles, Kai-Ren Ong, Jackie Cook, Fiona Douglas, Joan Paterson, M. John Kennedy, Zosia Miedzybrodzka, Andrew Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Muriel Belotti, Carole Tirapo, Sylvie Mazoyer, Laure Barjhoux, Christine Lasset, Dominique Leroux, Laurence Faivre, Myriam Bronner, Fabienne Prieur, Catherine Nogues, Etienne Rouleau, Pascal Pujol, Isabelle Coupier, Marc Frénay, John L. Hopper, Mary B. Daly, Mary B. Terry, Esther M. John, Saundra S. Buys, Yosuf Yassin, Alexander Miron, David Goldgar, Christian F. Singer, Muy-Kheng Tea, Georg Pfeiler, Anne Catharina Dressler, Thomas v. O. Hansen, Lars Jønson, Bent Ejlertsen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Kenneth Offit, Marion Piedmonte, Gustavo Rodriguez, Laurie Small, John Boggess, Stephanie Blank, Jack Basil, Masoud Azodi, Amanda Ewart Toland, Marco Montagna, Silvia Tognazzo, Simona Agata, Evgeny Imyanitov, Ramunas Janavicius, Conxi Lazaro, Ignacio Blanco, Paul D. P. Pharoah, Lara Sucheston, Beth Y. Karlan, Christine S. Walsh, Edith Olah, Aniko Bozsik, Soo-Hwang Teo, Joyce L. Seldon, Mary S. Beattie, Elizabeth J. van Rensburg, Michelle D. Sluiter, Orland Diez, Rita K. Schmutzler, Barbara Wappenschmidt, Christoph Engel, Alfons Meindl, Ina Ruehl, Raymonda Varon-Mateeva, Karin Kast, Helmut Deissler, Dieter Niederacher, Norbert Arnold, Dorothea Gadzicki, Ines Schönbuchner, Trinidad Caldes, Miguel de La Hoya, Heli Nevanlinna, Kristiina Aittomäki, Martine Dumont, Jocelyne Chiquette, Marc Tischkowitz, Xiaoqing Chen, Jonathan Beesley, Amanda B. Spurdle, Susan L. Neuhausen, Yuan Chun Ding, Zachary Fredericksen, Xianshu Wang, Vernon S. Pankratz, Fergus Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 15th Aug 2011

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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