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Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

2014; BioMed Central; Volume: 16; Issue: 6 Linguagem: Inglês

10.1186/s13058-014-0474-y

1465-542X

Amanda B. Spurdle, Fergus J. Couch, Michael T. Parsons, Lesley McGuffog, Daniel Barrowdale, Manjeet K. Bolla, Qin Wang, Sue Healey, Rita K. Schmutzler, Barbara Wappenschmidt, Kerstin Rhiem, Eric Hahnen, Christoph Engel, Alfons Meindl, Nina Ditsch, Norbert Arnold, Hansjoerg Plendl, Dieter Niederacher, Christian Sutter, Shan Wang‐Gohrke, Doris Steinemann, Sabine Preisler-Adams, Karin Kast, Raymonda Varon-Mateeva, Ian O. Ellis, Debra Frost, Radka Platte, Jo Perkins, D. Gareth Evans, Louise Izatt, Rosalind A. Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Giulietta Scuvera, Siranoush Manoukian, Bernardo Bonanni, Frédérique Mariette, Stefano Fortuzzi, Alessandra Viel, Barbara Pasini, Laura Papi, Liliana Varesco, Rosemary L. Balleine, Katherine L. Nathanson, Susan M. Domchek, Kenneth Offitt, Anna Jakubowska, Noralane M. Lindor, Mads Thomassen, Uffe Birk Jensen, Johanna Rantala, Åke Borg, Irene L. Andrulis, Alexander Miron, Thomas van Overeem Hansen, Trinidad Caldés, Susan L. Neuhausen, Amanda E. Toland, Heli Nevanlinna, Marco Montagna, Judy Garber, Andrew K. Godwin, Ana Osório, Rachel E. Factor, Mary Beth Terry, Timothy R. Rebbeck, Beth Y. Karlan, Melissa C. Southey, Muhammad Usman Rashid, Nadine Tung, Paul D.P. Pharoah, Fiona M. Blows, Alison M. Dunning, Elena Provenzano, Per Hall, Kamila Czene, Marjanka K. Schmidt, Annegien Broeks, Sten Cornelissen, Senno Verhoef, Peter A. Fasching, Matthias W. Beckmann, Arif B. Ekici, Dennis J. Slamon, Stig E. Bojesen, Børge G. Nordestgaard, Sune F. Nielsen, Henrik Flyger, Jenny Chang‐Claude, Dieter Flesch‐Janys, Anja Rudolph, Petra Seibold, Kristiina Aittomäki, Taru Muranen, Päivi Heikkilä, Carl Blomqvist, Jonine D. Figueroa, Stephen J. Chanock, Louise A. Brinton, Jolanta Lissowska, Janet E. Olson, V. Shane Pankratz, Esther M. John, Alice S. Whittemore, Dee W. West, Ute Hamann, Diana Torres, Hans Ulrich Ulmer, Thomas Rüdiger, Peter Devilee, Robert A.E.M. Tollenaar, Caroline Seynaeve, Christi J. van Asperen, Diana Eccles, William Tapper, Lorraine Durcan, J. Louise Jones, Julian Peto, Isabel dos‐Santos‐Silva, Olivia Fletcher, Nichola Johnson, Miriam Dwek, Ruth Swann, Anita Bane, Gord Glendon, Anna Marie Mulligan, Graham G. Giles, Roger L. Milne, Laura Baglietto, Catriona McLean, Jane Carpenter, Christine L. Clarke, Rodney J. Scott, Hiltrud Brauch, Thomas Brüning, Yon‐Dschun Ko, Angela Cox, Simon S. Cross, Malcolm Reed, Jan Lubiński, Katarzyna Jaworska–Bieniek, Katarzyna Durda, Jacek Gronwald, Thilo Dörk, Natalia Bogdanova, Tjoung‐Won Park‐Simon, Peter Hillemanns, Christopher A. Haiman, Brian E. Henderson, Fredrick R. Schumacher, Loı̈c Le Marchand, Barbara Burwinkel, Frederik Marmé, Harald Surovy, Rongxi Yang, Hoda Anton‐Culver, Argyrios Ziogas, Maartje J. Hooning, J. Margriet Collée, John W.M. Martens, Madeleine M.A. Tilanus‐Linthorst, Hermann Brenner, Aida Karina Dieffenbach, V Arndt, Christa Stegmaier, Robert Winqvist, Katri Pylkäs, Arja Jukkola‐Vuorinen, Mervi Grip, Annika Lindblom, Sara Margolin, Joseph Vijai, Mark E. Robson, Rohini Rau‐Murthy, Anna González‐Neira, José Ignacio Arias, Pilar Zamora, Javier Benı́tez, Graham J. Mann, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Paolo Peterlongo, Daniela Zaffaroni, Monica Barile, F Capra, Paolo Radice, Soo‐Hwang Teo, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix‐Trench, David E. Goldgar,

Cancer Genomics and Diagnostics

Abstract Introduction The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1 /2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach. Results ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2 , ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)). Conclusions These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.