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Identification of a DMBT1 polymorphism associated with increased breast cancer risk and decreased promoter activity
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

According to present estimations, the unfavorable combination of alleles with low penetrance but high prevalence in the population might account for the major part of hereditary breast cancer risk. … Deleted in Malignant Brain Tumors 1 (DMBT1) has been proposed as a tumor suppressor for breast cancer and other cancer types. Genomewide mapping in mice further identified Dmbt1 as a potential modulator of breast cancer risk. Here, we report the association of two frequent and linked single-nucleotide polymorphisms (SNPs) with increased breast cancer risk in women above the age of 60 years: DMBT1 c.-93C\textgreaterT, rs2981745, located in the DMBT1 promoter; and DMBT1 c.124A\textgreaterC, p.Thr42Pro, rs11523871(odds ratio [OR]=1.66, 95% confidence interval [CI]=1.21-2.29, P=0.0017; and OR=1.66; 95% CI=1.21-2.28, P=0.0016, respectively), based on 1,195 BRCA1/2 mutation-negative German breast cancer families and 1,466 unrelated German controls. Promoter studies in breast cancer cells demonstrate that the risk-increasing DMBT1 -93T allele displays significantly decreased promoter activity compared to the DMBT1 -93C allele, resulting in a loss of promoter activity. The data suggest that DMBT1 polymorphisms in the 5’-region are associated with increased breast cancer risk. In accordance with previous results, these data link decreased DMBT1 levels to breast cancer risk.

Authors: Sandrine Tchatchou, Angela Riedel, Stefan Lyer, Julia Schmutzhard, Olga Strobel-Freidekind, Sabine Gronert-Sum, Carola Mietag, Mauro D’Amato, Bettina Schlehe, Kari Hemminki, Christian Sutter, Nina Ditsch, Anneke Blackburn, Linda Zhai Hill, D. Joseph Jerry, Peter Bugert, Bernhard H. F. Weber, Dieter Niederacher, Norbert Arnold, Raymonda Varon-Mateeva, Barbara Wappenschmidt, Rita K. Schmutzler, Christoph Engel, Alfons Meindl, Claus R. Bartram, Jan Mollenhauer, Barbara Burwinkel

Date Published: 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Low-risk variants FGFR2, TNRC9 and LSP1 in German familial breast cancer patients
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

To validate common low-risk variants predisposing for breast cancer (BC) in a large set of BRCA1/2 negative familial or genetically enriched cases from Germany, we genotyped 1,415 cases and 1,830 healthy … women by MALDI-TOF in 105 candidate SNPs. Significantly higher ORs than previously reported for heterozygous unselected cases were found for the minor allele in FGFR2 (OR = 1.43, 95% CI 1.30-1.59, p-value = 1.24 x 10(-12)) and for TNRC9 (OR = 1.33, 95% CI 1.19-1.46, p-value = 1.54 x 10(-7)). Most intriguing, however, were the ORs for homozygous carriers from high-risk families for FGFR2 (OR = 2.05, 95% CI 1.68-2.51, LSP1 (OR = 0.49, 95% CI 0.28-0.86) and TNRC9 (OR = 1.62, 95% CI 1.27-2.07). Moreover, the additional validation of 99 CGEMS-SNPs identified putative novel susceptibility alleles within the LSP1 gene (OR = 0.73, 95% CI 0.61-0.87, p-value = 5.23 x 10(-4)). Finally, we provide evidence for the first time that a low-risk variant located at 6q22.33 (rs6569479) is associated with estrogen receptor negative BC in familial cases (OR = 1.33, 95% CI 1.06-1.66; p-value = 0.012). Our data confirm the impact of the previously identified susceptibility loci and provide preliminary evidence for novel susceptibility loci in familial BC cases and correlate them to specific histopathological subtypes defined by estrogen receptor status.

Authors: Kari Hemminki, Bertram Müller-Myhsok, Peter Lichtner, Christoph Engel, Bowang Chen, Barbara Burwinkel, Asta Försti, Christian Sutter, Barbara Wappenschmidt, Heide Hellebrand, Thomas Illig, Norbert Arnold, Dieter Niederacher, Bernd Dworniczak, Helmut Deissler, Karin Kast, Dorothea Gadzicki, Thomas Meitinger, H-Erich Wichmann, Marion Kiechle, Claus R. Bartram, Rita K. Schmutzler, Alfons Meindl

Date Published: 2010

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE To estimate the risk for contralateral breast cancer in members of BRCA1- and BRCA2-positive families and to determine predictive risk factors. PATIENTS AND METHODS A retrospective, multicenter, …er, cohort study was performed from 1996 until 2008 and comprised 2,020 women with unilateral breast cancer (index patients, n = 978; relatives, n = 1.42) from 978 families who had a BRCA1 or BRCA2 mutation. Cox regression analysis was applied to assess the association of age at first breast cancer with time from first to contralateral breast cancer, stratified by the affected BRCA gene. RESULTS The cumulative risk for contralateral breast cancer 25 years after first breast cancer was 47.4% (95% CI, 38.8% to 56.0%) for patients from families with BRCA1 or BRCA2 mutations. Members of families with BRCA1 mutations had a 1.6-fold (95% CI, 1.2-fold to 2.3-fold) higher risk of contralateral breast cancer than members of families with BRCA2 mutations. Younger age at first breast cancer was associated with a significantly higher risk of contralateral breast cancer in patients with BRCA1 mutation, and a trend was observed in patients with BRCA2 mutation. After 25 years, 62.9% (95% CI, 50.4% to 75.4%) of patients with BRCA1 mutation who were younger than 40 years of age at first breast cancer developed contralateral breast cancer, compared with only 19.6% (95% CI, 5.3% to 33.9%) of those who were older than 50 years of age at first breast cancer. CONCLUSION Contralateral breast cancer risk depends on age at first breast cancer and on the affected BRCA gene, and this risk should be considered in treatment planning.

Authors: Monika K. Graeser, Christoph Engel, Kerstin Rhiem, Dorothea Gadzicki, Ulrich Bick, Karin Kast, Ursula G. Froster, Bettina Schlehe, Astrid Bechtold, Norbert Arnold, Sabine Preisler-Adams, Carolin Nestle-Kraemling, Mohammad Zaino, Markus Loeffler, Marion Kiechle, Alfons Meindl, Dominic Varga, Rita K. Schmutzler

Date Published: 10th Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND In this study we aimed to evaluate the role of a SNP in intron 1 of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general …l population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out.

Authors: A. Osorio, R. L. Milne, G. Pita, P. Peterlongo, T. Heikkinen, J. Simard, G. Chenevix-Trench, A. B. Spurdle, J. Beesley, X. Chen, S. Healey, S. L. Neuhausen, Y. C. Ding, F. J. Couch, X. Wang, N. Lindor, S. Manoukian, M. Barile, A. Viel, L. Tizzoni, C. I. Szabo, L. Foretova, M. Zikan, K. Claes, M. H. Greene, P. Mai, G. Rennert, F. Lejbkowicz, O. Barnett-Griness, I. L. Andrulis, H. Ozcelik, N. Weerasooriya, A-M Gerdes, M. Thomassen, D. G. Cruger, M. A. Caligo, E. Friedman, B. Kaufman, Y. Laitman, S. Cohen, T. Kontorovich, R. Gershoni-Baruch, E. Dagan, H. Jernström, M. S. Askmalm, B. Arver, B. Malmer, S. M. Domchek, K. L. Nathanson, J. Brunet, T. Ramón Y Cajal, D. Yannoukakos, U. Hamann, F. B. L. Hogervorst, S. Verhoef, E. B. Gómez García, J. T. Wijnen, A. van den Ouweland, D. F. Easton, S. Peock, M. Cook, C. T. Oliver, D. Frost, C. Luccarini, D. G. Evans, F. Lalloo, R. Eeles, G. Pichert, J. Cook, S. Hodgson, P. J. Morrison, F. Douglas, A. K. Godwin, O. M. Sinilnikova, L. Barjhoux, D. Stoppa-Lyonnet, V. Moncoutier, S. Giraud, C. Cassini, L. Olivier-Faivre, F. Révillion, J-P Peyrat, D. Muller, J-P Fricker, H. T. Lynch, E. M. John, S. Buys, M. Daly, J. L. Hopper, M. B. Terry, A. Miron, Y. Yassin, D. Goldgar, C. F. Singer, D. Gschwantler-Kaulich, G. Pfeiler, A-C Spiess, Thomas v. O. Hansen, O. T. Johannsson, T. Kirchhoff, K. Offit, K. Kosarin, M. Piedmonte, G. C. Rodriguez, K. Wakeley, J. F. Boggess, J. Basil, P. E. Schwartz, S. V. Blank, A. E. Toland, M. Montagna, C. Casella, E. N. Imyanitov, A. Allavena, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Ditsch, N. Arnold, D. Niederacher, H. Deissler, B. Fiebig, R. Varon-Mateeva, D. Schaefer, U. G. Froster, T. Caldes, M. de La Hoya, L. McGuffog, A. C. Antoniou, H. Nevanlinna, P. Radice, J. Benítez

Date Published: 1st Dec 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Common variants in LSP1, 2q35 and 8q24 and breast cancer risk for BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Genome-wide association studies of breast cancer have identified multiple single nucleotide polymorphisms (SNPs) that are associated with increased breast cancer risks in the general population. In a … previous study, we demonstrated that the minor alleles at three of these SNPs, in FGFR2, TNRC9 and MAP3K1, also confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. Three additional SNPs rs3817198 at LSP1, rs13387042 at 2q35 and rs13281615 at 8q24 have since been reported to be associated with breast cancer in the general population, and in this study we evaluated their association with breast cancer risk in 9442 BRCA1 and 5665 BRCA2 mutation carriers from 33 study centres. The minor allele of rs3817198 was associated with increased breast cancer risk only for BRCA2 mutation carriers [hazard ratio (HR) = 1.16, 95% CI: 1.07-1.25, P-trend = 2.8 x 10(-4)]. The best fit for the association of SNP rs13387042 at 2q35 with breast cancer risk was a dominant model for both BRCA1 and BRCA2 mutation carriers (BRCA1: HR = 1.14, 95% CI: 1.04-1.25, P = 0.0047; BRCA2: HR = 1.18 95% CI: 1.04-1.33, P = 0.0079). SNP rs13281615 at 8q24 was not associated with breast cancer for either BRCA1 or BRCA2 mutation carriers, but the estimated association for BRCA2 mutation carriers (per-allele HR = 1.06, 95% CI: 0.98-1.14) was consistent with odds ratio estimates derived from population-based case-control studies. The LSP1 and 2q35 SNPs appear to interact multiplicatively on breast cancer risk for BRCA2 mutation carriers. There was no evidence that the associations vary by mutation type depending on whether the mutated protein is predicted to be stable or not.

Authors: Antonis C. Antoniou, Olga M. Sinilnikova, Lesley McGuffog, Sue Healey, Heli Nevanlinna, Tuomas Heikkinen, Jacques Simard, Amanda B. Spurdle, Jonathan Beesley, Xiaoqing Chen, Susan L. Neuhausen, Yuan C. Ding, Fergus J. Couch, Xianshu Wang, Zachary Fredericksen, Paolo Peterlongo, Bernard Peissel, Bernardo Bonanni, Alessandra Viel, Loris Bernard, Paolo Radice, Csilla I. Szabo, Lenka Foretova, Michal Zikan, Kathleen Claes, Mark H. Greene, Phuong L. Mai, Gad Rennert, Flavio Lejbkowicz, Irene L. Andrulis, Hilmi Ozcelik, Gord Glendon, Anne-Marie Gerdes, Mads Thomassen, Lone Sunde, Maria A. Caligo, Yael Laitman, Tair Kontorovich, Shimrit Cohen, Bella Kaufman, Efrat Dagan, Ruth Gershoni Baruch, Eitan Friedman, Katja Harbst, Gisela Barbany-Bustinza, Johanna Rantala, Hans Ehrencrona, Per Karlsson, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Ignacio Blanco, Adriana Lasa, Javier Benítez, Ute Hamann, Frans B. L. Hogervorst, Matti A. Rookus, J. Margriet Collee, Peter Devilee, Marjolijn J. Ligtenberg, Rob B. van der Luijt, Cora M. Aalfs, Quinten Waisfisz, Juul Wijnen, Cornelis E. P. van Roozendaal, Susan Peock, Margaret Cook, Debra Frost, Clare Oliver, Radka Platte, D. Gareth Evans, Fiona Lalloo, Rosalind Eeles, Louise Izatt, Rosemarie Davidson, Carol Chu, Diana Eccles, Trevor Cole, Shirley Hodgson, Andrew K. Godwin, Dominique Stoppa-Lyonnet, Bruno Buecher, Mélanie Léoné, Brigitte Bressac-de Paillerets, Audrey Remenieras, Olivier Caron, Gilbert M. Lenoir, Nicolas Sevenet, Michel Longy, Sandra Fert Ferrer, Fabienne Prieur, David Goldgar, Alexander Miron, Esther M. John, Saundra S. Buys, Mary B. Daly, John L. Hopper, Mary Beth Terry, Yosuf Yassin, Christian Singer, Daphne Gschwantler-Kaulich, Christine Staudigl, Thomas v. O. Hansen, Rosa Bjork Barkardottir, Tomas Kirchhoff, Prodipto Pal, Kristi Kosarin, Kenneth Offit, Marion Piedmonte, Gustavo C. Rodriguez, Katie Wakeley, John F. Boggess, Jack Basil, Peter E. Schwartz, Stephanie V. Blank, Amanda E. Toland, Marco Montagna, Cinzia Casella, Evgeny N. Imyanitov, Anna Allavena, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Dieter Niederacher, Helmut Deissler, Britta Fiebig, Christian Suttner, Ines Schönbuchner, Dorothea Gadzicki, Trinidad Caldes, Miguel de La Hoya, Karen A. Pooley, Douglas F. Easton, Georgia Chenevix-Trench

Date Published: 15th Nov 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Polymorphisms in BRCA2 resulting in aberrant codon-usage and their analysis on familial breast cancer risk
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Mutations in BRCA1 and BRCA2 are associated with increased breast cancer risk. While numerous non-synonymous SNPs in BRCA1/2 have been investigated for breast cancer risk, the impact of synonymous SNPs … has not been studied so far. Recently, it has been reported that synonymous SNPs leading to an aberration from the preferred codon-usage can have functional effects and consequently be associated with disease. This motivated us to search for SNPs with the tendency to differential codon-usage in BRCA1/BRCA2. Based on defined criteria, two codon-usage-changing variants, Ser455Ser (1365A \textgreater G) and Ser2414Ser (7242A \textgreater G), were detected in BRCA2, whereas no such variant could be identified in BRCA1. We investigated the impact of these variants on breast cancer risk in a large case-control study. However, both SNPs, BRCA2 Ser2414Ser (7242A \textgreater G) and Ser455Ser (1365A \textgreater G), showed no association with breast cancer risk. This indicates that these codon-usage-changing SNPs have no major impact on familial breast cancer risk.

Authors: Rongxi Yang, Bowang Chen, Kari Hemminki, Barbara Wappenschmidt, Christoph Engel, Christian Sutter, Nina Ditsch, Bernhard H. F. Weber, Dieter Niederacher, Norbert Arnold, Alfons Meindl, Claus R. Bartram, Rita K. Schmutzler, Barbara Burwinkel

Date Published: 1st Nov 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

The TP53 Arg72Pro and MDM2 309GT polymorphisms are not associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. …. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T\textgreaterG, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance. METHODS To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T\textgreaterG SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework. RESULTS No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association. CONCLUSION There was no evidence that TP53 Arg72Pro or MDM2 309T\textgreaterG, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers.

Authors: O. M. Sinilnikova, A. C. Antoniou, J. Simard, S. Healey, M. Léoné, D. Sinnett, A. B. Spurdle, J. Beesley, X. Chen, M. H. Greene, J. T. Loud, F. Lejbkowicz, G. Rennert, S. Dishon, I. L. Andrulis, S. M. Domchek, K. L. Nathanson, S. Manoukian, P. Radice, I. Konstantopoulou, I. Blanco, A. L. Laborde, M. Durán, A. Osorio, J. Benitez, U. Hamann, F. B. L. Hogervorst, T. A. M. van Os, H. J. P. Gille, S. Peock, M. Cook, C. Luccarini, D. G. Evans, F. Lalloo, R. Eeles, G. Pichert, R. Davidson, T. Cole, J. Cook, J. Paterson, C. Brewer, D. J. Hughes, I. Coupier, S. Giraud, F. Coulet, C. Colas, F. Soubrier, E. Rouleau, I. Bièche, R. Lidereau, L. Demange, C. Nogues, H. T. Lynch, R. K. Schmutzler, B. Versmold, C. Engel, A. Meindl, N. Arnold, C. Sutter, H. Deissler, D. Schaefer, U. G. Froster, K. Aittomäki, H. Nevanlinna, L. McGuffog, D. F. Easton, G. Chenevix-Trench, D. Stoppa-Lyonnet

Date Published: 1st Oct 2009

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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