Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
Creators: name: Spurdle, Amanda B.
name: Couch, Fergus J.
name: Parsons, Michael T.
name: McGuffog, Lesley
name: Barrowdale, Daniel
name: Bolla, Manjeet K.
name: Wang, Qin
name: Healey, Sue
name: Schmutzler, Rita Katharina
name: Wappenschmidt, Barbara
name: Rhiem, Kerstin
name: Hahnen, Eric
name: Engel, Christoph
name: Meindl, Alfons
name: Ditsch, Nina
name: Arnold, Norbert
name: Plendl, Hansjoerg
name: Niederacher, Dieter
name: Sutter, Christian
name: Wang-Gohrke, Shan
name: Steinemann, Doris
name: Preisler-Adams, Sabine
name: Kast, Karin
name: Varon-Mateeva, Raymonda
name: Ellis, Steve
name: Frost, Debra
name: Platte, Radka
name: Perkins, Jo
name: Evans, D Gareth
name: Davidson, Rosemarie
name: Izatt, Louise
name: Eeles, Ros
name: Adlard, Julian
name: Cole, Trevor
name: Scuvera, Giulietta
name: Manoukian, Siranoush
name: Bonanni, Bernardo
name: Mariette, Frederique
name: Fortuzzi, Stefano
name: Viel, Alessandra
name: Pasini, Barbara
name: Papi, Laura
name: Nathanson, Katherine L.
name: Varesco, Liliana
name: Balleine, Rosemary
name: Offit, Kenneth
name: Domchek, Susan M.
name: Jakubowska, Anna
name: Lindor, Noralane
name: Thomassen, Mads
name: Jensen, Uffe Birk
name: Rantala, Johanna
name: Miron, Alexander
name: Borg, Åke
name: Andrulis, Irene L.
name: Caldes, Trinidad
name: Hansen, Thomas V. O.
name: Neuhausen, Susan L.
name: Toland, Amanda E.
name: Nevanlinna, Heli
name: Montagna, Marco
name: Godwin, Andrew K.
name: Garber, Judy
name: Osorio, Ana
name: Factor, Rachel E.
name: Terry, Mary Beth
name: Rebbeck, Timothy R.
name: Karlan, Beth Y.
name: Southey, Melissa
name: Rashid, Muhammad Usman
name: Tung, Nadine
name: Pharoah, Paul D. P.
name: Blows, Fiona M.
name: Provenzano, Elena
name: Dunning, Alison M.
name: Hall, Per
name: Czene, Kamila
name: Schmidt, Marjanka K.
name: Broeks, Annegien
name: Verhoef, Senno
name: Cornelissen, Sten
name: Fasching, Peter A.
name: Beckmann, Matthias W.
name: Ekici, Arif B.
name: Slamon, Dennis J.
name: Nordestgaard, Børge G.
name: Nielsen, Sune F.
name: Bojesen, Stig E.
name: Flyger, Henrik
name: Chang-Claude, Jenny
name: Flesch-Janys, Dieter
name: Rudolph, Anja
name: Seibold, Petra
name: Aittomäki, Kristiina
name: Muranen, Taru A.
name: Heikkilä, Päivi
name: Blomqvist, Carl
name: Chanock, Stephen J.
name: Figueroa, Jonine
name: Brinton, Louise
name: Lissowska, Jolanta
name: Olson, Janet E.
name: Pankratz, Vernon S.
name: John, Esther M.
name: West, Dee W.
name: Whittemore, Alice S.
name: Hamann, Ute
name: Torres, Diana
name: Ulmer, Hans Ulrich
name: Rüdiger, Thomas
name: Devilee, Peter
name: Tollenaar, Robert A. E. M.
name: Seynaeve, Caroline
name: Asperen, Christi J. Van
name: Eccles, Diana M.
name: Tapper, William J.
name: Durcan, Lorraine
name: Jones, Louise
name: Peto, Julian
name: Dos-Santos-Silva, Isabel
name: Fletcher, Olivia
name: Johnson, Nichola
name: Dwek, Miriam
name: Bane, Anita L.
name: Swann, Ruth
name: Glendon, Gord
name: Mulligan, Anna M.
name: Giles, Graham G.
name: Milne, Roger L.
name: Baglietto, Laura
name: McLean, Catriona
name: Carpenter, Jane
name: Clarke, Christine
name: Scott, Rodney
name: Brüning, Thomas
name: Brauch, Hiltrud
name: Ko, Yon-Dschun
name: Cox, Angela
name: Cross, Simon S.
name: Reed, Malcolm W. R.
name: Jaworska-Bieniek, Katarzyna
name: Lubinski, Jan
name: Durda, Katarzyna
name: Gronwald, Jacek
name: Dörk, Thilo
name: Bogdanova, Natalia
name: Park-Simon, Tjoung-Won
name: Hillemanns, Peter
name: Haiman, Christopher A.
name: Henderson, Brian E.
name: Schumacher, Fredrick
name: Le Marchand, Loic
name: Marme, Frederik
name: Burwinkel, Barbara
name: Yang, Rongxi
name: Surovy, Harald
name: Anton-Culver, Hoda
name: Ziogas, Argyrios
name: Hooning, Maartje J.
name: Collée, Margriet
name: Martens, John W. M.
name: Tilanus-Linthorst, Madeleine M. A.
name: Brenner, Hermann
name: Dieffenbach, Aida Karina
name: Arndt, Volke
name: Stegmaier, Christa
name: Jukkola-Vuorinen, Arja
name: Pylkäs, Katri
name: Winqvist, Robert
name: Grip, Mervi
name: Lindblom, Annika
name: Margolin, Sara
name: Joseph, Vijai
name: González-Neira, Anna
name: Rau-Murthy, Rohini
name: Robson, Mark
name: Arias, José Ignacio
name: Zamora, Pilar
name: Benítez, Javier
name: Mannermaa, Arto
name: Kataja, Vesa
name: Kosma, Veli-Matti
name: Hartikainen, Jaana M.
name: Peterlongo, Paolo
name: Peterlongo, Paolo
name: Zaffaroni, Daniela
name: Capra, Fabio
name: Barile, Monica
name: Radice, Paolo
name: Teo, Soo H.
name: Easton, Douglas F.
name: Chenevix-Trench, Georgia
name: Antoniou, Antonis C.
name: Goldgar, David E.
Publisher: name: Columbia University
Year: 2014
Subjects: subject: Breast--Histopathology
subject: Mutation (Biology)
subject: Breast--Tumors
subject: Genetics
subject: FOS: Biological sciences
subject: Oncology

description: 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.