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 Loman; Katja 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

doi:10.1001/jama.2014.5985

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

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

328 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 language	English
Pages (from-to)	1347-1361
Journal	JAMA - Journal of the American Medical Association
Volume	313
Issue number	13
DOIs	https://doi.org/10.1001/jama.2014.5985
Publication status	Published - 7 Apr 2015

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1001/jama.2014.5985

Cite this

Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Chenevix-Trench, G., Easton, D. F., Antoniou, A. C., Nathanson, K. L., Laitman, Y., Kushnir, A., Paluch-Shimon, S., Berger, R., Zidan, J., Friedman, E., Ehrencrona, H., Stenmark-Askmalm, M., Einbeigi, Z., ... Cook, J. (2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA - Journal of the American Medical Association, 313(13), 1347-1361. https://doi.org/10.1001/jama.2014.5985

@article{5df103b5f16842c9a2faa4e96c313513,

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 Janavi{\v c}ius 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",

year = "2015",

month = apr,

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",

}

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 2015, 'Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer', JAMA - Journal of the American Medical Association, vol. 313, no. 13, pp. 1347-1361. https://doi.org/10.1001/jama.2014.5985

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

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.

U2 - 10.1001/jama.2014.5985

DO - 10.1001/jama.2014.5985

M3 - Article

SN - 0002-9955

VL - 313

SP - 1347

EP - 1361

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

IS - 13

ER -

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

Abstract

UN SDGs

Access to Document

Fingerprint

Cite this