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Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

  • Author(s): Rebbeck, Timothy R
  • Mitra, Nandita
  • Wan, Fei
  • Sinilnikova, Olga M
  • Healey, Sue
  • McGuffog, Lesley
  • Mazoyer, Sylvie
  • Chenevix-Trench, Georgia
  • Easton, Douglas F
  • Antoniou, Antonis C
  • Nathanson, Katherine L
  • CIMBA Consortium
  • Laitman, Yael
  • Kushnir, Anya
  • Paluch-Shimon, Shani
  • Berger, Raanan
  • Zidan, Jamal
  • Friedman, Eitan
  • Ehrencrona, Hans
  • Stenmark-Askmalm, Marie
  • Einbeigi, Zakaria
  • Loman, Niklas
  • Harbst, Katja
  • Rantala, Johanna
  • Melin, Beatrice
  • Huo, Dezheng
  • Olopade, Olufunmilayo I
  • Seldon, Joyce
  • Ganz, Patricia A
  • Nussbaum, Robert L
  • Chan, Salina B
  • Odunsi, Kunle
  • Gayther, Simon A
  • Domchek, Susan M
  • Arun, Banu K
  • Lu, Karen H
  • Mitchell, Gillian
  • Karlan, Beth Y
  • Walsh, Christine
  • Lester, Jenny
  • Godwin, Andrew K
  • Pathak, Harsh
  • Ross, Eric
  • Daly, Mary B
  • Whittemore, Alice S
  • John, Esther M
  • Miron, Alexander
  • Terry, Mary Beth
  • Chung, Wendy K
  • Goldgar, David E
  • Buys, Saundra S
  • Janavicius, Ramunas
  • Tihomirova, Laima
  • Tung, Nadine
  • Dorfling, Cecilia M
  • van Rensburg, Elizabeth J
  • Steele, Linda
  • Neuhausen, Susan L
  • Ding, Yuan Chun
  • Ejlertsen, Bent
  • Gerdes, Anne-Marie
  • Hansen, Thomas VO
  • Ramón y Cajal, Teresa
  • Osorio, Ana
  • Benitez, Javier
  • Godino, Javier
  • Tejada, Maria-Isabel
  • Duran, Mercedes
  • Weitzel, Jeffrey N
  • Bobolis, Kristie A
  • Sand, Sharon R
  • Fontaine, Annette
  • Savarese, Antonella
  • Pasini, Barbara
  • Peissel, Bernard
  • Bonanni, Bernardo
  • Zaffaroni, Daniela
  • Vignolo-Lutati, Francesca
  • Scuvera, Giulietta
  • Giannini, Giuseppe
  • Bernard, Loris
  • Genuardi, Maurizio
  • Radice, Paolo
  • Dolcetti, Riccardo
  • Manoukian, Siranoush
  • Pensotti, Valeria
  • Gismondi, Viviana
  • Yannoukakos, Drakoulis
  • Fostira, Florentia
  • Garber, Judy
  • Torres, Diana
  • Rashid, Muhammad Usman
  • Hamann, Ute
  • Peock, Susan
  • Frost, Debra
  • Platte, Radka
  • Evans, D Gareth
  • Eeles, Rosalind
  • Davidson, Rosemarie
  • Eccles, Diana
  • Cole, Trevor
  • Cook, Jackie
  • Brewer, Carole
  • Hodgson, Shirley
  • Morrison, Patrick J
  • Walker, Lisa
  • Porteous, Mary E
  • Kennedy, M John
  • Izatt, Louise
  • Adlard, Julian
  • Donaldson, Alan
  • Ellis, Steve
  • Sharma, Priyanka
  • Schmutzler, Rita Katharina
  • Wappenschmidt, Barbara
  • Becker, Alexandra
  • Rhiem, Kerstin
  • Hahnen, Eric
  • Engel, Christoph
  • Meindl, Alfons
  • Engert, Stefanie
  • Ditsch, Nina
  • Arnold, Norbert
  • Plendl, Hans Jörg
  • Mundhenke, Christoph
  • Niederacher, Dieter
  • Fleisch, Markus
  • Sutter, Christian
  • Bartram, CR
  • Dikow, Nicola
  • Wang-Gohrke, Shan
  • Gadzicki, Dorothea
  • Steinemann, Doris
  • Kast, Karin
  • Beer, Marit
  • Varon-Mateeva, Raymonda
  • Gehrig, Andrea
  • Weber, Bernhard H
  • Stoppa-Lyonnet, Dominique
  • Sinilnikova, Olga M
  • Mazoyer, Sylvie
  • Houdayer, Claude
  • Belotti, Muriel
  • Gauthier-Villars, Marion
  • Damiola, Francesca
  • Boutry-Kryza, Nadia
  • Lasset, Christine
  • Sobol, Hagay
  • Peyrat, Jean-Philippe
  • Muller, Danièle
  • Fricker, Jean-Pierre
  • Collonge-Rame, Marie-Agnès
  • Mortemousque, Isabelle
  • Nogues, Catherine
  • Rouleau, Etienne
  • Isaacs, Claudine
  • De Paepe, Anne
  • Poppe, Bruce
  • Claes, Kathleen
  • De Leeneer, Kim
  • Piedmonte, Marion
  • Rodriguez, Gustavo
  • Wakely, Katie
  • Boggess, John
  • Blank, Stephanie V
  • Basil, Jack
  • Azodi, Masoud
  • Phillips, Kelly-Anne
  • Caldes, Trinidad
  • de la Hoya, Miguel
  • Romero, Atocha
  • Nevanlinna, Heli
  • Aittomäki, Kristiina
  • van der Hout, Annemarie H
  • Hogervorst, Frans BL
  • Verhoef, Senno
  • Collée, J Margriet
  • Seynaeve, Caroline
  • Oosterwijk, Jan C
  • Gille, Johannes JP
  • Wijnen, Juul T
  • Gómez Garcia, Encarna B
  • Kets, Carolien M
  • Ausems, Margreet GEM
  • Aalfs, Cora M
  • Devilee, Peter
  • Mensenkamp, Arjen R
  • Kwong, Ava
  • Olah, Edith
  • Papp, Janos
  • Diez, Orland
  • Lazaro, Conxi
  • Darder, Esther
  • Blanco, Ignacio
  • Salinas, Mónica
  • Jakubowska, Anna
  • Lubinski, Jan
  • Gronwald, Jacek
  • Jaworska-Bieniek, Katarzyna
  • Durda, Katarzyna
  • Sukiennicki, Grzegorz
  • Huzarski, Tomasz
  • Byrski, Tomasz
  • Cybulski, Cezary
  • Toloczko-Grabarek, Aleksandra
  • Złowocka-Perłowska, Elżbieta
  • Menkiszak, Janusz
  • Arason, Adalgeir
  • Barkardottir, Rosa B
  • Simard, Jacques
  • Laframboise, Rachel
  • Montagna, Marco
  • Agata, Simona
  • Alducci, Elisa
  • Peixoto, Ana
  • Teixeira, Manuel R
  • Spurdle, Amanda B
  • Lee, Min Hyuk
  • Park, Sue K
  • Kim, Sung-Won
  • Friebel, Tara M
  • Couch, Fergus J
  • Lindor, Noralane M
  • Pankratz, Vernon S
  • Guidugli, Lucia
  • Wang, Xianshu
  • Tischkowitz, Marc
  • Foretova, Lenka
  • Vijai, Joseph
  • Offit, Kenneth
  • Robson, Mark
  • Rau-Murthy, Rohini
  • Kauff, Noah
  • Fink-Retter, Anneliese
  • Singer, Christian F
  • Rappaport, Christine
  • Gschwantler-Kaulich, Daphne
  • Pfeiler, Georg
  • Tea, Muy-Kheng
  • Berger, Andreas
  • Greene, Mark H
  • Mai, Phuong L
  • Imyanitov, Evgeny N
  • Toland, Amanda Ewart
  • Senter, Leigha
  • Bojesen, Anders
  • Pedersen, Inge Sokilde
  • Skytte, Anne-Bine
  • Sunde, Lone
  • Thomassen, Mads
  • Moeller, Sanne Traasdahl
  • Kruse, Torben A
  • Jensen, Uffe Birk
  • Caligo, Maria Adelaide
  • Aretini, Paolo
  • Teo, Soo-Hwang
  • Selkirk, Christina G
  • Hulick, Peter J
  • Andrulis, Irene
  • et al.

Published Web Location

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4537700/pdf/nihms693111.pdf
No data is associated with this publication.
Abstract

IMPORTANCE:Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. OBJECTIVE:To identify mutation-specific cancer risks for carriers of BRCA1/2. DESIGN, SETTING, AND PARTICIPANTS:Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. EXPOSURES:Mutations of BRCA1 or BRCA2. MAIN OUTCOMES AND MEASURES:Breast and ovarian cancer risks. RESULTS:Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95% CI, 1.22-1.74; P = 2 × 10(-6)), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95% CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95% CI, 1.22-1.55; P = 6 × 10(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95% CI, 0.56-0.70; P = 9 × 10(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95% CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95% CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95% CI, 1.69-3.16; P = .00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95% CI, 0.44-0.60; P = 6 × 10(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95% CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. CONCLUSIONS AND RELEVANCE:Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

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