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

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

Research output: Contribution to journalArticle

170 Citations (Scopus)

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 ofwomen whowere 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.

Original languageEnglish
Pages (from-to)1347-1361
Number of pages15
JournalJournal of the American Medical Association
Volume313
Issue number13
DOIs
Publication statusPublished - Apr 7 2015

Fingerprint

Ovarian Neoplasms
Breast Neoplasms
Mutation
Neoplasms
Second Primary Neoplasms
Nonsense Codon
Observational Studies
Exons
Decision Making
Breast
Nucleotides
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., ... Andrulis, I. (2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. Journal of the American Medical Association, 313(13), 1347-1361. https://doi.org/10.1001/jama.2014.5985

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; 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.; Janavičius, 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; Ramon 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 Jorg; 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; Belotti, Muriel; Gauthier-Villars, Marion; Damiola, Francesca; Boutry-Kryza, Nadia; Lasset, Christine; Sobol, Hagay; Peyrat, Jean Philippe; Muller, Daniele; Fricker, Jean Pierre; Collonge-Rame, Marie Agnes; 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; Aittomaki, Kristiina; Van Der Hout, Annemarie H.; Hogervorst, Frans B L; Verhoef, Senno; Collee, J. Margriet; Seynaeve, Caroline; Oosterwijk, Jan C.; Gille, Johannes J P; Wijnen, Juul T.; Gomez Garcia, Encarna B.; 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, Monica; Jakubowska, Anna; Lubinski, Jan; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sukiennicki, Grzegorz; Huzarski, Tomasz; Byrski, Tomasz; Cybulski, Cezary; Toloczko-Grabarek, Aleksandra; Złowocka-Perłowska, Elzbieta; 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.

In: Journal of the American Medical Association, Vol. 313, No. 13, 07.04.2015, p. 1347-1361.

Research output: Contribution to journalArticle

Rebbeck, TR, Mitra, N, Wan, F, Sinilnikova, OM, Healey, S, McGuffog, L, Chenevix-Trench, G, Easton, DF, Antoniou, AC, Nathanson, KL, Laitman, Y, Kushnir, A, Paluch-Shimon, S, Berger, R, Zidan, J, Friedman, E, Ehrencrona, H, Stenmark-Askmalm, M, Einbeigi, Z, Loman, N, Harbst, K, Rantala, J, Melin, B, Huo, D, Olopade, OI, Seldon, J, Ganz, PA, Nussbaum, RL, Chan, SB, Odunsi, K, Gayther, SA, Domchek, SM, Arun, BK, Lu, KH, Mitchell, G, Karlan, BY, Walsh, C, Lester, J, Godwin, AK, Pathak, H, Ross, E, Daly, MB, Whittemore, AS, John, EM, Miron, A, Terry, MB, Chung, WK, Goldgar, DE, Buys, SS, Janavičius, R, Tihomirova, L, Tung, N, Dorfling, CM, Van Rensburg, EJ, Steele, L, Neuhausen, SL, Ding, YC, Ejlertsen, B, Gerdes, AM, Hansen, TVO, Ramon Y Cajal, T, Osorio, A, Benitez, J, Godino, J, Tejada, MI, Duran, M, Weitzel, JN, Bobolis, KA, Sand, SR, Fontaine, A, Savarese, A, Pasini, B, Peissel, B, Bonanni, B, Zaffaroni, D, Vignolo-Lutati, F, Scuvera, G, Giannini, G, Bernard, L, Genuardi, M, Radice, P, Dolcetti, R, Manoukian, S, Pensotti, V, Gismondi, V, Yannoukakos, D, Fostira, F, Garber, J, Torres, D, Rashid, MU, Hamann, U, Peock, S, Frost, D, Platte, R, Evans, DG, Eeles, R, Davidson, R, Eccles, D, Cole, T, Cook, J, Brewer, C, Hodgson, S, Morrison, PJ, Walker, L, Porteous, ME, Kennedy, MJ, Izatt, L, Adlard, J, Donaldson, A, Ellis, S, Sharma, P, Schmutzler, RK, Wappenschmidt, B, Becker, A, Rhiem, K, Hahnen, E, Engel, C, Meindl, A, Engert, S, Ditsch, N, Arnold, N, Plendl, HJ, Mundhenke, C, Niederacher, D, Fleisch, M, Sutter, C, Bartram, CR, Dikow, N, Wang-Gohrke, S, Gadzicki, D, Steinemann, D, Kast, K, Beer, M, Varon-Mateeva, R, Gehrig, A, Weber, BH, Stoppa-Lyonnet, D, Belotti, M, Gauthier-Villars, M, Damiola, F, Boutry-Kryza, N, Lasset, C, Sobol, H, Peyrat, JP, Muller, D, Fricker, JP, Collonge-Rame, MA, Mortemousque, I, Nogues, C, Rouleau, E, Isaacs, C, De Paepe, A, Poppe, B, Claes, K, De Leeneer, K, Piedmonte, M, Rodriguez, G, Wakely, K, Boggess, J, Blank, SV, Basil, J, Azodi, M, Phillips, KA, Caldes, T, De La Hoya, M, Romero, A, Nevanlinna, H, Aittomaki, K, Van Der Hout, AH, Hogervorst, FBL, Verhoef, S, Collee, JM, Seynaeve, C, Oosterwijk, JC, Gille, JJP, Wijnen, JT, Gomez Garcia, EB, Kets, CM, Ausems, MGEM, Aalfs, CM, Devilee, P, Mensenkamp, AR, Kwong, A, Olah, E, Papp, J, Diez, O, Lazaro, C, Darder, E, Blanco, I, Salinas, M, Jakubowska, A, Lubinski, J, Gronwald, J, Jaworska-Bieniek, K, Durda, K, Sukiennicki, G, Huzarski, T, Byrski, T, Cybulski, C, Toloczko-Grabarek, A, Złowocka-Perłowska, E, Menkiszak, J, Arason, A, Barkardottir, RB, Simard, J, Laframboise, R, Montagna, M, Agata, S, Alducci, E, Peixoto, A, Teixeira, MR, Spurdle, AB, Lee, MH, Park, SK, Kim, SW, Friebel, TM, Couch, FJ, Lindor, NM, Pankratz, VS, Guidugli, L, Wang, X, Tischkowitz, M, Foretova, L, Vijai, J, Offit, K, Robson, M, Rau-Murthy, R, Kauff, N, Fink-Retter, A, Singer, CF, Rappaport, C, Gschwantler-Kaulich, D, Pfeiler, G, Tea, MK, Berger, A, Greene, MH, Mai, PL, Imyanitov, EN, Toland, AE, Senter, L, Bojesen, A, Pedersen, IS, Skytte, AB, Sunde, L, Thomassen, M, Moeller, ST, Kruse, TA, Jensen, UB, Caligo, MA, Aretini, P, Teo, SH, Selkirk, CG, Hulick, PJ & Andrulis, I 2015, 'Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer', Journal of the American Medical Association, vol. 313, no. 13, pp. 1347-1361. https://doi.org/10.1001/jama.2014.5985
Rebbeck, Timothy R. ; Mitra, Nandita ; Wan, Fei ; Sinilnikova, Olga M. ; Healey, Sue ; McGuffog, Lesley ; 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. ; Janavičius, 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 ; Ramon 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 Jorg ; 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 ; Belotti, Muriel ; Gauthier-Villars, Marion ; Damiola, Francesca ; Boutry-Kryza, Nadia ; Lasset, Christine ; Sobol, Hagay ; Peyrat, Jean Philippe ; Muller, Daniele ; Fricker, Jean Pierre ; Collonge-Rame, Marie Agnes ; 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 ; Aittomaki, Kristiina ; Van Der Hout, Annemarie H. ; Hogervorst, Frans B L ; Verhoef, Senno ; Collee, J. Margriet ; Seynaeve, Caroline ; Oosterwijk, Jan C. ; Gille, Johannes J P ; Wijnen, Juul T. ; Gomez Garcia, Encarna B. ; 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, Monica ; Jakubowska, Anna ; Lubinski, Jan ; Gronwald, Jacek ; Jaworska-Bieniek, Katarzyna ; Durda, Katarzyna ; Sukiennicki, Grzegorz ; Huzarski, Tomasz ; Byrski, Tomasz ; Cybulski, Cezary ; Toloczko-Grabarek, Aleksandra ; Złowocka-Perłowska, Elzbieta ; 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. / Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. In: Journal of the American Medical Association. 2015 ; Vol. 313, No. 13. pp. 1347-1361.
@article{c62347369daf48aaaa666f068aab6807,
title = "Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer",
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 ofwomen whowere 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.",
author = "Rebbeck, {Timothy R.} and Nandita Mitra and Fei Wan and Sinilnikova, {Olga M.} and Sue Healey and Lesley McGuffog and Georgia Chenevix-Trench and Easton, {Douglas F.} and Antoniou, {Antonis C.} and Nathanson, {Katherine L.} and Yael Laitman and Anya Kushnir and Shani Paluch-Shimon and Raanan Berger and Jamal Zidan and Eitan Friedman and Hans Ehrencrona and Marie Stenmark-Askmalm and Zakaria Einbeigi and Niklas Loman and Katja Harbst and Johanna Rantala and Beatrice Melin and Dezheng Huo and Olopade, {Olufunmilayo I.} and Joyce Seldon and Ganz, {Patricia A.} and Nussbaum, {Robert L.} and Chan, {Salina B.} and Kunle Odunsi and Gayther, {Simon A.} and Domchek, {Susan M.} and Arun, {Banu K.} and Lu, {Karen H.} and Gillian Mitchell and Karlan, {Beth Y.} and Christine Walsh and Jenny Lester and Godwin, {Andrew K.} and Harsh Pathak and Eric Ross and Daly, {Mary B.} and Whittemore, {Alice S.} and John, {Esther M.} and Alexander Miron and Terry, {Mary Beth} and Chung, {Wendy K.} and Goldgar, {David E.} and Buys, {Saundra S.} and Ramunas Janavičius and Laima Tihomirova and Nadine Tung and Dorfling, {Cecilia M.} and {Van Rensburg}, {Elizabeth J.} and Linda Steele and Neuhausen, {Susan L.} and Ding, {Yuan Chun} and Bent Ejlertsen and Gerdes, {Anne Marie} and Hansen, {Thomas V O} and {Ramon Y Cajal}, Teresa and Ana Osorio and Javier Benitez and Javier Godino and Tejada, {Maria Isabel} and Mercedes Duran and Weitzel, {Jeffrey N.} and Bobolis, {Kristie A.} and Sand, {Sharon R.} and Annette Fontaine and Antonella Savarese and Barbara Pasini and Bernard Peissel and Bernardo Bonanni and Daniela Zaffaroni and Francesca Vignolo-Lutati and Giulietta Scuvera and Giuseppe Giannini and Loris Bernard and Maurizio Genuardi and Paolo Radice and Riccardo Dolcetti and Siranoush Manoukian and Valeria Pensotti and Viviana Gismondi and Drakoulis Yannoukakos and Florentia Fostira and Judy Garber and Diana Torres and Rashid, {Muhammad Usman} and Ute Hamann and Susan Peock and Debra Frost and Radka Platte and Evans, {D. Gareth} and Rosalind Eeles and Rosemarie Davidson and Diana Eccles and Trevor Cole and Jackie Cook and Carole Brewer and Shirley Hodgson and Morrison, {Patrick J.} and Lisa Walker and Porteous, {Mary E.} and Kennedy, {M. John} and Louise Izatt and Julian Adlard and Alan Donaldson and Steve Ellis and Priyanka Sharma and Schmutzler, {Rita Katharina} and Barbara Wappenschmidt and Alexandra Becker and Kerstin Rhiem and Eric Hahnen and Christoph Engel and Alfons Meindl and Stefanie Engert and Nina Ditsch and Norbert Arnold and Plendl, {Hans Jorg} and Christoph Mundhenke and Dieter Niederacher and Markus Fleisch and Christian Sutter and Bartram, {C. R.} and Nicola Dikow and Shan Wang-Gohrke and Dorothea Gadzicki and Doris Steinemann and Karin Kast and Marit Beer and Raymonda Varon-Mateeva and Andrea Gehrig and Weber, {Bernhard H.} and Dominique Stoppa-Lyonnet and Muriel Belotti and Marion Gauthier-Villars and Francesca Damiola and Nadia Boutry-Kryza and Christine Lasset and Hagay Sobol and Peyrat, {Jean Philippe} and Daniele Muller and Fricker, {Jean Pierre} and Collonge-Rame, {Marie Agnes} and Isabelle Mortemousque and Catherine Nogues and Etienne Rouleau and Claudine Isaacs and {De Paepe}, Anne and Bruce Poppe and Kathleen Claes and {De Leeneer}, Kim and Marion Piedmonte and Gustavo Rodriguez and Katie Wakely and John Boggess and Blank, {Stephanie V.} and Jack Basil and Masoud Azodi and Phillips, {Kelly Anne} and Trinidad Caldes and {De La Hoya}, Miguel and Atocha Romero and Heli Nevanlinna and Kristiina Aittomaki and {Van Der Hout}, {Annemarie H.} and Hogervorst, {Frans B L} and Senno Verhoef and Collee, {J. Margriet} and Caroline Seynaeve and Oosterwijk, {Jan C.} and Gille, {Johannes J P} and Wijnen, {Juul T.} and {Gomez Garcia}, {Encarna B.} and Kets, {Carolien M.} and Ausems, {Margreet G E M} and Aalfs, {Cora M.} and Peter Devilee and Mensenkamp, {Arjen R.} and Ava Kwong and Edith Olah and Janos Papp and Orland Diez and Conxi Lazaro and Esther Darder and Ignacio Blanco and Monica Salinas and Anna Jakubowska and Jan Lubinski and Jacek Gronwald and Katarzyna Jaworska-Bieniek and Katarzyna Durda and Grzegorz Sukiennicki and Tomasz Huzarski and Tomasz Byrski and Cezary Cybulski and Aleksandra Toloczko-Grabarek and Elzbieta Złowocka-Perłowska and Janusz Menkiszak and Adalgeir Arason and Barkardottir, {Rosa B.} and Jacques Simard and Rachel Laframboise and Marco Montagna and Simona Agata and Elisa Alducci and Ana Peixoto and Teixeira, {Manuel R.} and Spurdle, {Amanda B.} and Lee, {Min Hyuk} and Park, {Sue K.} and Kim, {Sung Won} and Friebel, {Tara M.} and Couch, {Fergus J.} and Lindor, {Noralane M.} and Pankratz, {Vernon S.} and Lucia Guidugli and Xianshu Wang and Marc Tischkowitz and Lenka Foretova and Joseph Vijai and Kenneth Offit and Mark Robson and Rohini Rau-Murthy and Noah Kauff and Anneliese Fink-Retter and Singer, {Christian F.} and Christine Rappaport and Daphne Gschwantler-Kaulich and Georg Pfeiler and Tea, {Muy Kheng} and Andreas Berger and Greene, {Mark H.} and Mai, {Phuong L.} and Imyanitov, {Evgeny N.} and Toland, {Amanda Ewart} and Leigha Senter and Anders Bojesen and Pedersen, {Inge Sokilde} and Skytte, {Anne Bine} and Lone Sunde and Mads Thomassen and Moeller, {Sanne Traasdahl} and Kruse, {Torben A.} and Jensen, {Uffe Birk} and Caligo, {Maria Adelaide} and Paolo Aretini and Teo, {Soo Hwang} and Selkirk, {Christina G.} and Hulick, {Peter J.} and Irene Andrulis",
year = "2015",
month = "4",
day = "7",
doi = "10.1001/jama.2014.5985",
language = "English",
volume = "313",
pages = "1347--1361",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "13",

}

TY - JOUR

T1 - Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer

AU - Rebbeck, Timothy R.

AU - Mitra, Nandita

AU - Wan, Fei

AU - Sinilnikova, Olga M.

AU - Healey, Sue

AU - McGuffog, Lesley

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

AU - Antoniou, Antonis C.

AU - Nathanson, Katherine L.

AU - Laitman, Yael

AU - Kushnir, Anya

AU - Paluch-Shimon, Shani

AU - Berger, Raanan

AU - Zidan, Jamal

AU - Friedman, Eitan

AU - Ehrencrona, Hans

AU - Stenmark-Askmalm, Marie

AU - Einbeigi, Zakaria

AU - Loman, Niklas

AU - Harbst, Katja

AU - Rantala, Johanna

AU - Melin, Beatrice

AU - Huo, Dezheng

AU - Olopade, Olufunmilayo I.

AU - Seldon, Joyce

AU - Ganz, Patricia A.

AU - Nussbaum, Robert L.

AU - Chan, Salina B.

AU - Odunsi, Kunle

AU - Gayther, Simon A.

AU - Domchek, Susan M.

AU - Arun, Banu K.

AU - Lu, Karen H.

AU - Mitchell, Gillian

AU - Karlan, Beth Y.

AU - Walsh, Christine

AU - Lester, Jenny

AU - Godwin, Andrew K.

AU - Pathak, Harsh

AU - Ross, Eric

AU - Daly, Mary B.

AU - Whittemore, Alice S.

AU - John, Esther M.

AU - Miron, Alexander

AU - Terry, Mary Beth

AU - Chung, Wendy K.

AU - Goldgar, David E.

AU - Buys, Saundra S.

AU - Janavičius, Ramunas

AU - Tihomirova, Laima

AU - Tung, Nadine

AU - Dorfling, Cecilia M.

AU - Van Rensburg, Elizabeth J.

AU - Steele, Linda

AU - Neuhausen, Susan L.

AU - Ding, Yuan Chun

AU - Ejlertsen, Bent

AU - Gerdes, Anne Marie

AU - Hansen, Thomas V O

AU - Ramon Y Cajal, Teresa

AU - Osorio, Ana

AU - Benitez, Javier

AU - Godino, Javier

AU - Tejada, Maria Isabel

AU - Duran, Mercedes

AU - Weitzel, Jeffrey N.

AU - Bobolis, Kristie A.

AU - Sand, Sharon R.

AU - Fontaine, Annette

AU - Savarese, Antonella

AU - Pasini, Barbara

AU - Peissel, Bernard

AU - Bonanni, Bernardo

AU - Zaffaroni, Daniela

AU - Vignolo-Lutati, Francesca

AU - Scuvera, Giulietta

AU - Giannini, Giuseppe

AU - Bernard, Loris

AU - Genuardi, Maurizio

AU - Radice, Paolo

AU - Dolcetti, Riccardo

AU - Manoukian, Siranoush

AU - Pensotti, Valeria

AU - Gismondi, Viviana

AU - Yannoukakos, Drakoulis

AU - Fostira, Florentia

AU - Garber, Judy

AU - Torres, Diana

AU - Rashid, Muhammad Usman

AU - Hamann, Ute

AU - Peock, Susan

AU - Frost, Debra

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Eeles, Rosalind

AU - Davidson, Rosemarie

AU - Eccles, Diana

AU - Cole, Trevor

AU - Cook, Jackie

AU - Brewer, Carole

AU - Hodgson, Shirley

AU - Morrison, Patrick J.

AU - Walker, Lisa

AU - Porteous, Mary E.

AU - Kennedy, M. John

AU - Izatt, Louise

AU - Adlard, Julian

AU - Donaldson, Alan

AU - Ellis, Steve

AU - Sharma, Priyanka

AU - Schmutzler, Rita Katharina

AU - Wappenschmidt, Barbara

AU - Becker, Alexandra

AU - Rhiem, Kerstin

AU - Hahnen, Eric

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Engert, Stefanie

AU - Ditsch, Nina

AU - Arnold, Norbert

AU - Plendl, Hans Jorg

AU - Mundhenke, Christoph

AU - Niederacher, Dieter

AU - Fleisch, Markus

AU - Sutter, Christian

AU - Bartram, C. R.

AU - Dikow, Nicola

AU - Wang-Gohrke, Shan

AU - Gadzicki, Dorothea

AU - Steinemann, Doris

AU - Kast, Karin

AU - Beer, Marit

AU - Varon-Mateeva, Raymonda

AU - Gehrig, Andrea

AU - Weber, Bernhard H.

AU - Stoppa-Lyonnet, Dominique

AU - Belotti, Muriel

AU - Gauthier-Villars, Marion

AU - Damiola, Francesca

AU - Boutry-Kryza, Nadia

AU - Lasset, Christine

AU - Sobol, Hagay

AU - Peyrat, Jean Philippe

AU - Muller, Daniele

AU - Fricker, Jean Pierre

AU - Collonge-Rame, Marie Agnes

AU - Mortemousque, Isabelle

AU - Nogues, Catherine

AU - Rouleau, Etienne

AU - Isaacs, Claudine

AU - De Paepe, Anne

AU - Poppe, Bruce

AU - Claes, Kathleen

AU - De Leeneer, Kim

AU - Piedmonte, Marion

AU - Rodriguez, Gustavo

AU - Wakely, Katie

AU - Boggess, John

AU - Blank, Stephanie V.

AU - Basil, Jack

AU - Azodi, Masoud

AU - Phillips, Kelly Anne

AU - Caldes, Trinidad

AU - De La Hoya, Miguel

AU - Romero, Atocha

AU - Nevanlinna, Heli

AU - Aittomaki, Kristiina

AU - Van Der Hout, Annemarie H.

AU - Hogervorst, Frans B L

AU - Verhoef, Senno

AU - Collee, J. Margriet

AU - Seynaeve, Caroline

AU - Oosterwijk, Jan C.

AU - Gille, Johannes J P

AU - Wijnen, Juul T.

AU - Gomez Garcia, Encarna B.

AU - Kets, Carolien M.

AU - Ausems, Margreet G E M

AU - Aalfs, Cora M.

AU - Devilee, Peter

AU - Mensenkamp, Arjen R.

AU - Kwong, Ava

AU - Olah, Edith

AU - Papp, Janos

AU - Diez, Orland

AU - Lazaro, Conxi

AU - Darder, Esther

AU - Blanco, Ignacio

AU - Salinas, Monica

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Gronwald, Jacek

AU - Jaworska-Bieniek, Katarzyna

AU - Durda, Katarzyna

AU - Sukiennicki, Grzegorz

AU - Huzarski, Tomasz

AU - Byrski, Tomasz

AU - Cybulski, Cezary

AU - Toloczko-Grabarek, Aleksandra

AU - Złowocka-Perłowska, Elzbieta

AU - Menkiszak, Janusz

AU - Arason, Adalgeir

AU - Barkardottir, Rosa B.

AU - Simard, Jacques

AU - Laframboise, Rachel

AU - Montagna, Marco

AU - Agata, Simona

AU - Alducci, Elisa

AU - Peixoto, Ana

AU - Teixeira, Manuel R.

AU - Spurdle, Amanda B.

AU - Lee, Min Hyuk

AU - Park, Sue K.

AU - Kim, Sung Won

AU - Friebel, Tara M.

AU - Couch, Fergus J.

AU - Lindor, Noralane M.

AU - Pankratz, Vernon S.

AU - Guidugli, Lucia

AU - Wang, Xianshu

AU - Tischkowitz, Marc

AU - Foretova, Lenka

AU - Vijai, Joseph

AU - Offit, Kenneth

AU - Robson, Mark

AU - Rau-Murthy, Rohini

AU - Kauff, Noah

AU - Fink-Retter, Anneliese

AU - Singer, Christian F.

AU - Rappaport, Christine

AU - Gschwantler-Kaulich, Daphne

AU - Pfeiler, Georg

AU - Tea, Muy Kheng

AU - Berger, Andreas

AU - Greene, Mark H.

AU - Mai, Phuong L.

AU - Imyanitov, Evgeny N.

AU - Toland, Amanda Ewart

AU - Senter, Leigha

AU - Bojesen, Anders

AU - Pedersen, Inge Sokilde

AU - Skytte, Anne Bine

AU - Sunde, Lone

AU - Thomassen, Mads

AU - Moeller, Sanne Traasdahl

AU - Kruse, Torben A.

AU - Jensen, Uffe Birk

AU - Caligo, Maria Adelaide

AU - Aretini, Paolo

AU - Teo, Soo Hwang

AU - Selkirk, Christina G.

AU - Hulick, Peter J.

AU - Andrulis, Irene

PY - 2015/4/7

Y1 - 2015/4/7

N2 - 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 ofwomen whowere 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.

AB - 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 ofwomen whowere 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.

UR - http://www.scopus.com/inward/record.url?scp=84927556016&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84927556016&partnerID=8YFLogxK

U2 - 10.1001/jama.2014.5985

DO - 10.1001/jama.2014.5985

M3 - Article

C2 - 25849179

AN - SCOPUS:84927556016

VL - 313

SP - 1347

EP - 1361

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 13

ER -