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- PMID: 25849179
- UKPMCID: 25849179
- DOI: 10.1001/jama.2014.5985
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Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.
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; ; 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 v O; 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, C R; 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 B L; Verhoef, Senno; Collée, J Margriet; Seynaeve, Caroline; Oosterwijk, Jan C; Gille, Johannes J P; Wijnen, Juul T; Garcia, Encarna B Gómez; Kets, Carolien M; Ausems, Margreet G E M; 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
JAMA. 2015;313(13):1347-61.
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Full-text held externally
- PMID: 25849179
- UKPMCID: 25849179
- DOI: 10.1001/jama.2014.5985
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.
Bibliographic metadata
- 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
- 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 v O
- 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, C R
- 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 B L
- Verhoef, Senno
- Collée, J Margriet
- Seynaeve, Caroline
- Oosterwijk, Jan C
- Gille, Johannes J P
- Wijnen, Juul T
- Garcia, Encarna B Gómez
- Kets, Carolien M
- Ausems, Margreet G E M
- 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