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99 Publications visible to you, out of a total of 99
No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The transforming growth factor beta-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and …d secretion of TGF-beta, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. METHODS To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. RESULTS We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92-1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81-1.04) in BRCA2 mutation carriers. CONCLUSIONS These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.

Authors: Timothy R. Rebbeck, Antonis C. Antoniou, Trinidad Caldes Llopis, Heli Nevanlinna, Kristiina Aittomäki, Jacques Simard, Amanda B. Spurdle, Fergus J. Couch, Lutecia H. Mateus Pereira, Mark H. Greene, Irene L. Andrulis, Boris Pasche, Virginia Kaklamani, Ute Hamann, Csilla Szabo, Susan Peock, Margaret Cook, Patricia A. Harrington, Alan Donaldson, Allison M. Male, Carol Anne Gardiner, Helen Gregory, Lucy E. Side, Anne C. Robinson, Louise Emmerson, Ian Ellis, Jean-Philippe Peyrat, Joëlle Fournier, Philippe Vennin, Claude Adenis, Danièle Muller, Jean-Pierre Fricker, Michel Longy, Olga M. Sinilnikova, Dominique Stoppa-Lyonnet, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Karin Kast, Dieter Schaefer, Ursula G. Froster, Georgia Chenevix-Trench, Douglas F. Easton

Date Published: 1st May 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Association of hormone receptor status with grading, age of onset, and tumor size in BRCA1-associated breast cancer
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BRCA1-associated breast cancer frequently presents with estrogen-receptor (ERalpha) and progesterone-receptor (PR) negativity, grade 3, and early onset. In contrast, in BRCA1-deficient mice, ERalpha … is highly expressed in early tumorigenesis. In a retrospective cohort study on 587 breast cancer patients with deleterious BRCA1 mutations, the correlation of ER, PR status, grading, age of onset, and tumor size was investigated. ERalpha and PR expression decreased from 62% in ductal carcinoma in situ (DCIS) to 20% and 16% in pT3, respectively (p value for ER 0.025 and PR 0.035, Fisher’s exact test). The percentage of grade 1/2 tumors decreased from 44% in DCIS to 17% in pT3 (p value 0.074). Moreover, ER/PR positivity increased with increasing age. Our data suggest that early stage BRCA1-associated breast cancers are more frequently ERalpha and PR positive and low grade than advanced stages.

Authors: M. Graeser, K. Bosse, M. Brosig, C. Engel, R. K. Schmutzler

Date Published: 1st May 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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

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

Association of the BRCA1 missense variant R1699W with a malignant phyllodes tumor of the breast
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Familial breast carcinomas that are attributable to BRCA1 or BRCA2 mutations have characteristic morphologic and immunhistochemical features. BRCA1-associated carcinomas are poorly differentiated … infiltrating ductal carcinomas frequently exhibiting morphologic features of typical or atypical medullary carcinomas such as prominent lymphocytic infiltrate and pushing margins. We report on a patient carrying the deleterious BRCA1 germline mutation R1699W, who presented with a malignant phyllodes tumor of the breast. The re-investigation of archival material by a reference pathologist of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) revealed BRCA-associated pronounced pushing margins. In a total of 618 unrelated index patients who are registered in the GCHBOC database, no other phyllodes tumor has been described, while 10 carriers of the R1699W mutant have been identified. We conclude that the histopathologic appearance of the phyllodes tumor indicates an association with the BRCA1 mutation R1699W although it is a rare event in BRCA-positive families.

Authors: Kerstin Rhiem, Uta Flucke, Christoph Engel, Barbara Wappenschmidt, Axel Reinecke-Lüthge, Reinhard Büttner, Rita Katharina Schmutzler

Date Published: 1st Jul 2007

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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