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Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA)
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. …. METHODS We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. RESULTS There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 \times 10(-5)), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 \times 10(-6)). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 \times 10(-13) for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 \times 10(-14)), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 \times 10(-15)). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). CONCLUSIONS/IMPACT: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

Authors: Nasim Mavaddat, Daniel Barrowdale, Irene L. Andrulis, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Amanda Spurdle, Mark Robson, Mark Sherman, Anna Marie Mulligan, Fergus J. Couch, Christoph Engel, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Melissa C. Southey, Mary Beth Terry, David Goldgar, Frances O’Malley, Esther M. John, Ramunas Janavicius, Laima Tihomirova, Thomas v. O. Hansen, Finn C. Nielsen, Ana Osorio, Alexandra Stavropoulou, Javier Benítez, Siranoush Manoukian, Bernard Peissel, Monica Barile, Sara Volorio, Barbara Pasini, Riccardo Dolcetti, Anna Laura Putignano, Laura Ottini, Paolo Radice, Ute Hamann, Muhammad U. Rashid, Frans B. Hogervorst, Mieke Kriege, Rob B. van der Luijt, Susan Peock, Debra Frost, D. Gareth Evans, Carole Brewer, Lisa Walker, Mark T. Rogers, Lucy E. Side, Catherine Houghton, JoEllen Weaver, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Karin Kast, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Doroteha Gadzicki, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schönbuchner, Heidrun Gevensleben, Dominique Stoppa-Lyonnet, Muriel Belotti, Laure Barjhoux, Claudine Isaacs, Beth N. Peshkin, Trinidad Caldes, Miguel de La Hoya, Carmen Cañadas, Tuomas Heikkinen, Päivi Heikkilä, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Bjarni A. Agnarsson, Adalgeir Arason, Rosa B. Barkardottir, Martine Dumont, Jacques Simard, Marco Montagna, Simona Agata, Emma D’Andrea, Max Yan, Stephen Fox, Timothy R. Rebbeck, Wendy Rubinstein, Nadine Tung, Judy E. Garber, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia M. Gaudet, Christian F. Singer, Muy-Kheng Tea, Christine Rappaport, Phuong L. Mai, Mark H. Greene, Anna Sokolenko, Evgeny Imyanitov, Amanda Ewart Toland, Leigha Senter, Kevin Sweet, Mads Thomassen, Anne-Marie Gerdes, Torben Kruse, Maria Caligo, Paolo Aretini, Johanna Rantala, Anna von Wachenfeld, Karin Henriksson, Linda Steele, Susan L. Neuhausen, Robert Nussbaum, Mary Beattie, Kunle Odunsi, Lara Sucheston, Simon A. Gayther, Kate Nathanson, Jenny Gross, Christine Walsh, Beth Karlan, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou

Date Published: 5th Jan 2012

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Performance of in silico prediction tools for the classification of rare BRCA1/2 missense variants in clinical diagnostics
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND The use of next-generation sequencing approaches in clinical diagnostics has led to a tremendous increase in data and a vast number of variants of uncertain significance that require …e interpretation. Therefore, prediction of the effects of missense mutations using in silico tools has become a frequently used approach. Aim of this study was to assess the reliability of in silico prediction as a basis for clinical decision making in the context of hereditary breast and/or ovarian cancer. METHODS We tested the performance of four prediction tools (Align-GVGD, SIFT, PolyPhen-2, MutationTaster2) using a set of 236 BRCA1/2 missense variants that had previously been classified by expert committees. However, a major pitfall in the creation of a reliable evaluation set for our purpose is the generally accepted classification of BRCA1/2 missense variants using the multifactorial likelihood model, which is partially based on Align-GVGD results. To overcome this drawback we identified 161 variants whose classification is independent of any previous in silico prediction. In addition to the performance as stand-alone tools we examined the sensitivity, specificity, accuracy and Matthews correlation coefficient (MCC) of combined approaches. RESULTS PolyPhen-2 achieved the lowest sensitivity (0.67), specificity (0.67), accuracy (0.67) and MCC (0.39). Align-GVGD achieved the highest values of specificity (0.92), accuracy (0.92) and MCC (0.73), but was outperformed regarding its sensitivity (0.90) by SIFT (1.00) and MutationTaster2 (1.00). All tools suffered from poor specificities, resulting in an unacceptable proportion of false positive results in a clinical setting. This shortcoming could not be bypassed by combination of these tools. In the best case scenario, 138 families would be affected by the misclassification of neutral variants within the cohort of patients of the German Consortium for Hereditary Breast and Ovarian Cancer. CONCLUSION We show that due to low specificities state-of-the-art in silico prediction tools are not suitable to predict pathogenicity of variants of uncertain significance in BRCA1/2. Thus, clinical consequences should never be based solely on in silico forecasts. However, our data suggests that SIFT and MutationTaster2 could be suitable to predict benignity, as both tools did not result in false negative predictions in our analysis.

Authors: Corinna Ernst, Eric Hahnen, Christoph Engel, Michael Nothnagel, Jonas Weber, Rita K. Schmutzler, Jan Hauke

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for … prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

Authors: Nasim Mavaddat, Kyriaki Michailidou, Joe Dennis, Michael Lush, Laura Fachal, Andrew Lee, Jonathan P. Tyrer, Ting-Huei Chen, Qin Wang, Manjeet K. Bolla, Xin Yang, Muriel A. Adank, Thomas Ahearn, Kristiina Aittomäki, Jamie Allen, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Päivi Auvinen, Myrto Barrdahl, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Michael Bremer, Hermann Brenner, Adam Brentnall, Ian W. Brock, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Daniele Campa, Brian D. Carter, Jose E. Castelao, Stephen J. Chanock, Rowan Chlebowski, Hans Christiansen, Christine L. Clarke, J. Margriet Collée, Emilie Cordina-Duverger, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel Dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Asta Försti, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Irina R. Gilyazova, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Steven N. Hart, Wei He, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Katarzyna Kaczmarek, Vesa Kataja, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Julia A. Knight, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Jenna Lilyquist, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W. M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Usha Menon, Pooja Middha, Nicola Miller, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Victor M. Muñoz-Garzon, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Kenneth Offit, Janet E. Olson, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I. A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Julian Peto, Mila Pinchev, Dijana Plaseska-Karanfilska, Eric C. Polley, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Kristen Purrington, Katri Pylkäs, Brigitte Rack, Paolo Radice, Rohini Rau-Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Mark Robson, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Caroline Seynaeve, Mitul Shah, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Susan Slager, Ann Smeets, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Jennifer Stone, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Kathrin Thöne, Rob A. E. M. Tollenaar, Ian Tomlinson, Thérèse Truong, Maria Tzardi, Hans-Ulrich Ulmer, Michael Untch, Celine M. Vachon, Elke M. van Veen, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Deborah J. Thompson, Georgia Chenevix-Trench, Jenny Chang-Claude, Marjanka K. Schmidt, Per Hall, Roger L. Milne, Paul D. P. Pharoah, Antonis C. Antoniou, Nilanjan Chatterjee, Peter Kraft, Montserrat García-Closas, Jacques Simard, Douglas F. Easton

Date Published: 2019

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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

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

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

Purpose BRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated-for the first … time to our knowledge-associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/ 2 mutations and implications for cancer risk prediction. Materials and Methods We genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights. Results In male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 \times 10-6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 \times 10-9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively. Conclusion PRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Authors: Julie Lecarpentier, Valentina Silvestri, Karoline B. Kuchenbaecker, Daniel Barrowdale, Joe Dennis, Lesley McGuffog, Penny Soucy, Goska Leslie, Piera Rizzolo, Anna Sara Navazio, Virginia Valentini, Veronica Zelli, Andrew Lee, Ali Amin Al Olama, Jonathan P. Tyrer, Melissa Southey, Esther M. John, Thomas A. Conner, David E. Goldgar, Saundra S. Buys, Ramunas Janavicius, Linda Steele, Yuan Chun Ding, Susan L. Neuhausen, Thomas v. O. Hansen, Ana Osorio, Jeffrey N. Weitzel, Angela Toss, Veronica Medici, Laura Cortesi, Ines Zanna, Domenico Palli, Paolo Radice, Siranoush Manoukian, Bernard Peissel, Jacopo Azzollini, Alessandra Viel, Giulia Cini, Giuseppe Damante, Stefania Tommasi, Paolo Peterlongo, Florentia Fostira, Ute Hamann, D. Gareth Evans, Alex Henderson, Carole Brewer, Diana Eccles, Jackie Cook, Kai-Ren Ong, Lisa Walker, Lucy E. Side, Mary E. Porteous, Rosemarie Davidson, Shirley Hodgson, Debra Frost, Julian Adlard, Louise Izatt, Ros Eeles, Steve Ellis, Marc Tischkowitz, Andrew K. Godwin, Alfons Meindl, Andrea Gehrig, Bernd Dworniczak, Christian Sutter, Christoph Engel, Dieter Niederacher, Doris Steinemann, Eric Hahnen, Jan Hauke, Kerstin Rhiem, Karin Kast, Norbert Arnold, Nina Ditsch, Shan Wang-Gohrke, Barbara Wappenschmidt, Dorothea Wand, Christine Lasset, Dominique Stoppa-Lyonnet, Muriel Belotti, Francesca Damiola, Laure Barjhoux, Sylvie Mazoyer, Mattias van Heetvelde, Bruce Poppe, Kim de Leeneer, Kathleen B. M. Claes, Miguel de La Hoya, Vanesa Garcia-Barberan, Trinidad Caldes, Pedro Perez Segura, Johanna I. Kiiski, Kristiina Aittomäki, Sofia Khan, Heli Nevanlinna, Christi J. van Asperen, Tibor Vaszko, Miklos Kasler, Edith Olah, Judith Balmaña, Sara Gutiérrez-Enríquez, Orland Diez, Alex Teulé, Angel Izquierdo, Esther Darder, Joan Brunet, Jesús Del Valle, Lidia Feliubadalo, Miquel Angel Pujana, Conxi Lazaro, Adalgeir Arason, Bjarni A. Agnarsson, Oskar Th Johannsson, Rosa B. Barkardottir, Elisa Alducci, Silvia Tognazzo, Marco Montagna, Manuel R. Teixeira, Pedro Pinto, Amanda B. Spurdle, Helene Holland, Jong Won Lee, Min Hyuk Lee, Jihyoun Lee, Sung-Won Kim, Eunyoung Kang, Zisun Kim, Priyanka Sharma, Timothy R. Rebbeck, Joseph Vijai, Mark Robson, Anne Lincoln, Jacob Musinsky, Pragna Gaddam, Yen Y. Tan, Andreas Berger, Christian F. Singer, Jennifer T. Loud, Mark H. Greene, Anna Marie Mulligan, Gord Glendon, Irene L. Andrulis, Amanda Ewart Toland, Leigha Senter, Anders Bojesen, Henriette Roed Nielsen, Anne-Bine Skytte, Lone Sunde, Uffe Birk Jensen, Inge Sokilde Pedersen, Lotte Krogh, Torben A. Kruse, Maria A. Caligo, Sook-Yee Yoon, Soo-Hwang Teo, Anna von Wachenfeldt, Dezheng Huo, Sarah M. Nielsen, Olufunmilayo I. Olopade, Katherine L. Nathanson, Susan M. Domchek, Christa Lorenchick, Rachel C. Jankowitz, Ian Campbell, Paul James, Gillian Mitchell, Nick Orr, Sue Kyung Park, Mads Thomassen, Kenneth Offit, Fergus J. Couch, Jacques Simard, Douglas F. Easton, Georgia Chenevix-Trench, Rita K. Schmutzler, Antonis C. Antoniou, Laura Ottini

Date Published: 10th Jul 2017

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

Prevalence of BRCA1/2 germline mutations in 21 401 families with breast and ovarian cancer.
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

PURPOSE: To characterise the prevalence of pathogenic germline mutations in BRCA1 and BRCA2 in families with breast cancer (BC) and ovarian cancer (OC) history. PATIENTS AND METHODS: Data from 21 401 … families were gathered between 1996 and 2014 in a clinical setting in the German Consortium for Hereditary Breast and Ovarian Cancer, comprising full pedigrees with cancer status of all individual members at the time of first counselling, and BRCA1/2 mutation status of the index patient. RESULTS: The overall BRCA1/2 mutation prevalence was 24.0% (95% CI 23.4% to 24.6%). Highest mutation frequencies were observed in families with at least two OCs (41.9%, 95% CI 36.1% to 48.0%) and families with at least one breast and one OC (41.6%, 95% CI 40.3% to 43.0%), followed by male BC with at least one female BC or OC (35.8%; 95% CI 32.2% to 39.6%). In families with a single case of early BC (<36 years), mutations were found in 13.7% (95% CI 11.9% to 15.7%). Postmenopausal unilateral or bilateral BC did not increase the probability of mutation detection. Occurrence of premenopausal BC and OC in the same woman led to higher mutation frequencies compared with the occurrence of these two cancers in different individuals (49.0%; 95% CI 41.0% to 57.0% vs 31.5%; 95% CI 28.0% to 35.2%). CONCLUSIONS: Our data provide guidance for healthcare professionals and decision-makers to identify individuals who should undergo genetic testing for hereditary breast and ovarian cancer. Moreover, it supports informed decision-making of counselees on the uptake of genetic testing.

Authors: K. Kast, K. Rhiem, B. Wappenschmidt, E. Hahnen, J. Hauke, B. Bluemcke, V. Zarghooni, N. Herold, N. Ditsch, M. Kiechle, M. Braun, C. Fischer, N. Dikow, S. Schott, N. Rahner, D. Niederacher, T. Fehm, A. Gehrig, C. Mueller-Reible, N. Arnold, N. Maass, G. Borck, N. de Gregorio, C. Scholz, B. Auber, R. Varon-Manteeva, D. Speiser, J. Horvath, N. Lichey, P. Wimberger, S. Stark, U. Faust, B. H. Weber, G. Emons, S. Zachariae, A. Meindl, R. K. Schmutzler, C. Engel

Date Published: 2nd Mar 2016

Publication Type: Journal article

Human Diseases: breast cancer, ovarian cancer

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history
GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Abstract (Expand)

BACKGROUND There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic …c testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. METHODS The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. RESULTS A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50-2.32, p \textless 0.001). gBRCA mutation risk was predicted to be \textgreater 10% for women diagnosed below approximately 50 years. CONCLUSIONS Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.

Authors: Christoph Engel, Kerstin Rhiem, Eric Hahnen, Sibylle Loibl, Karsten E. Weber, Sabine Seiler, Silke Zachariae, Jan Hauke, Barbara Wappenschmidt, Anke Waha, Britta Blümcke, Marion Kiechle, Alfons Meindl, Dieter Niederacher, Claus R. Bartram, Dorothee Speiser, Brigitte Schlegelberger, Norbert Arnold, Peter Wieacker, Elena Leinert, Andrea Gehrig, Susanne Briest, Karin Kast, Olaf Riess, Günter Emons, Bernhard H. F. Weber, Jutta Engel, Rita K. Schmutzler

Date Published: 1st Dec 2018

Publication Type: Journal article

Human Diseases: hereditary breast ovarian cancer syndrome

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