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; Bent Ejlertsen; Anne-Marie Gerdes; 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, Bent Ejlertsen, Anne-Marie Gerdes, CIMBA Consortium

245 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	J A M A: 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

Keywords

Adult
Age of Onset
Breast Neoplasms
Female
Genes, BRCA1
Genes, BRCA2
Genetic Predisposition to Disease
Heterozygote
Humans
Middle Aged
Mutation
Nucleotides
Ovarian Neoplasms
Risk Factors

UN SDGs

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

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10.1001/jama.2014.5985

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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. J A M A: The Journal of the American Medical Association, 313(13), 1347-61. https://doi.org/10.1001/jama.2014.5985

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, Ejlertsen, B , Gerdes, A-M & CIMBA Consortium 2015, 'Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer', J A M A: The Journal of the American Medical Association, vol. 313, no. 13, pp. 1347-61. https://doi.org/10.1001/jama.2014.5985

@article{123a3af3ad334ca092bd7b934a2c8949,

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.",

keywords = "Adult, Age of Onset, Breast Neoplasms, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Mutation, Nucleotides, Ovarian Neoplasms, Risk Factors",

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 Bent Ejlertsen and Anne-Marie Gerdes and {CIMBA Consortium}",

year = "2015",

month = apr,

day = "7",

doi = "10.1001/jama.2014.5985",

language = "English",

volume = "313",

pages = "1347--61",

journal = "J A M A: The Journal of the American Medical Association",

issn = "0098-7484",

publisher = "American Medical Association",

number = "13",

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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 - Ejlertsen, Bent

AU - Gerdes, Anne-Marie

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.

KW - Adult

KW - Age of Onset

KW - Breast Neoplasms

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Predisposition to Disease

KW - Heterozygote

KW - Humans

KW - Middle Aged

KW - Mutation

KW - Nucleotides

KW - Ovarian Neoplasms

KW - Risk Factors

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 - J A M A: The Journal of the American Medical Association

JF - J A M A: 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

Abstract

Keywords

UN SDGs

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