Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

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.

DOI: 10.1186/s13058-014-0474-y

Projects: GC-HBOC - German Consortium for Hereditary Breast and Ovarian Cancer

Publication type: Journal article

Journal: Breast cancer research : BCR

Human Diseases: Hereditary breast ovarian cancer syndrome

Citation: Breast Cancer Res 16(6),3419

Date Published: 1st Dec 2014

Registered Mode: imported from a bibtex file

Authors: Amanda B. Spurdle, Fergus J. Couch, Michael T. Parsons, Lesley McGuffog, Daniel Barrowdale, Manjeet K. Bolla, Qin Wang, Sue Healey, Rita 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, Steve Ellis, Debra Frost, Radka Platte, Jo Perkins, D. Gareth Evans, Louise Izatt, Ros Eeles, Julian Adlard, Rosemarie Davidson, Trevor Cole, Giulietta Scuvera, Siranoush Manoukian, Bernardo Bonanni, Frederique Mariette, Stefano Fortuzzi, Alessandra Viel, Barbara Pasini, Laura Papi, Liliana Varesco, Rosemary Balleine, Katherine L. Nathanson, Susan M. Domchek, Kenneth Offitt, Anna Jakubowska, Noralane Lindor, Mads Thomassen, Uffe Birk Jensen, Johanna Rantala, Åke Borg, Irene L. Andrulis, Alexander Miron, Thomas v. O. Hansen, Trinidad Caldes, Susan L. Neuhausen, Amanda E. Toland, Heli Nevanlinna, Marco Montagna, Judy Garber, Andrew K. Godwin, Ana Osorio, Rachel E. Factor, Mary B. Terry, Timothy R. Rebbeck, Beth Y. Karlan, Melissa 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 A. Muranen, Päivi Heikkilä, Carl Blomqvist, Jonine Figueroa, Stephen J. Chanock, Louise Brinton, Jolanta Lissowska, Janet E. Olson, Vernon S. 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 M. Eccles, William J. Tapper, Lorraine Durcan, Louise Jones, Julian Peto, Isabel Dos-Santos-Silva, Olivia Fletcher, Nichola Johnson, Miriam Dwek, Ruth Swann, Anita L. Bane, Gord Glendon, Anna M. Mulligan, Graham G. Giles, Roger L. Milne, Laura Baglietto, Catriona McLean, Jane Carpenter, Christine Clarke, Rodney Scott, Hiltrud Brauch, Thomas Brüning, Yon-Dschun Ko, Angela Cox, Simon S. Cross, Malcolm W. R. Reed, Jan Lubinski, Katarzyna Jaworska-Bieniek, Katarzyna Durda, Jacek Gronwald, Thilo Dörk, Natalia Bogdanova, Tjoung-Won Park-Simon, Peter Hillemanns, Christopher A. Haiman, Brian E. Henderson, Fredrick Schumacher, Loic Le Marchand, Barbara Burwinkel, Frederik Marme, 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, Volke Arndt, Christa Stegmaier, Robert Winqvist, Katri Pylkäs, Arja Jukkola-Vuorinen, Mervi Grip, Annika Lindblom, Sara Margolin, Vijai Joseph, Mark Robson, Rohini Rau-Murthy, Anna González-Neira, José Ignacio Arias, Pilar Zamora, Javier Benítez, Arto Mannermaa, Vesa Kataja, Veli-Matti Kosma, Jaana M. Hartikainen, Paolo Peterlongo, Daniela Zaffaroni, Monica Barile, Fabio Capra, Paolo Radice, Soo H. Teo, Douglas F. Easton, Antonis C. Antoniou, Georgia Chenevix-Trench, David E. Goldgar

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René Hänsel

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, Spurdle, A. B., , , , Couch, F. J., Parsons, M. T., McGuffog, L., Barrowdale, D., Bolla, M. K., Wang, Q., Healey, S., Schmutzler, R. K., Wappenschmidt, B., Rhiem, K., Hahnen, E., Engel, C., Meindl, A., Ditsch, N., … Goldgar, D. E. (2014). Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. In Breast Cancer Research (Vol. 16, Issue 6). Springer Science and Business Media LLC. https://doi.org/10.1186/s13058-014-0474-y

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Created: 15th Jul 2020 at 13:30

Last updated: 7th Dec 2021 at 17:58

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

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