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; Sylvie Mazoyer; 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; Inge Sokilde Pedersen; CIMBA Consortium

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, Sylvie Mazoyer, 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 EinbeigiNiklas 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, Inge Sokilde Pedersen, CIMBA Consortium

Research output: Contribution to journal › Journal article › Research › peer-review

370 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 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.

Original language	English
Journal	JAMA: The Journal of the American Medical Association
Volume	313
Issue number	13
Pages (from-to)	1347-61
Number of pages	15
ISSN	0098-7484
DOIs	https://doi.org/10.1001/jama.2014.5985
Publication status	Published - 7 Apr 2015

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Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., Mazoyer, S., 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., ... CIMBA Consortium (2015). Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. JAMA: The Journal of the American Medical Association, 313(13), 1347-61. https://doi.org/10.1001/jama.2014.5985

@article{6caaeb023cd440a28513641ca51bc006,

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 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.",

author = "Rebbeck, {Timothy R} and Nandita Mitra and Fei Wan and Sinilnikova, {Olga M} and Sue Healey and Lesley McGuffog and Sylvie Mazoyer 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 Pedersen, {Inge Sokilde} and {CIMBA Consortium}",

year = "2015",

month = apr,

day = "7",

doi = "10.1001/jama.2014.5985",

language = "English",

volume = "313",

pages = "1347--61",

journal = "JAMA: The Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "13",

}

Rebbeck, TR, Mitra, N, Wan, F, Sinilnikova, OM, Healey, S, McGuffog, L, Mazoyer, S, 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, Pedersen, IS & CIMBA Consortium 2015, 'Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer', JAMA: The Journal of the American Medical Association, vol. 313, no. 13, pp. 1347-61. 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 - Mazoyer, Sylvie

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 - Pedersen, Inge Sokilde

AU - CIMBA Consortium

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 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.

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 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.

U2 - 10.1001/jama.2014.5985

DO - 10.1001/jama.2014.5985

M3 - Journal article

C2 - 25849179

SN - 0098-7484

VL - 313

SP - 1347

EP - 1361

JO - JAMA: The Journal of the American Medical Association

JF - JAMA: The 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

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