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

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Harvard

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, Ejlertsen, B, Gerdes, A-M, Hansen, TVO & 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

APA

Rebbeck, T. R., Mitra, N., Wan, F., Sinilnikova, O. M., Healey, S., McGuffog, L., ... 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

CBE

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, Ejlertsen B, Gerdes A-M, Hansen TVO, 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

MLA

Vancouver

Author

Rebbeck, Timothy R ; Mitra, Nandita ; Wan, Fei ; Sinilnikova, Olga M ; Healey, Sue ; McGuffog, Lesley ; Mazoyer, Sylvie ; Chenevix-Trench, Georgia ; Easton, Douglas F ; Antoniou, Antonis C ; Nathanson, Katherine L ; Laitman, Yael ; Kushnir, Anya ; Paluch-Shimon, Shani ; Berger, Raanan ; Zidan, Jamal ; Friedman, Eitan ; Ehrencrona, Hans ; Stenmark-Askmalm, Marie ; Einbeigi, Zakaria ; Loman, Niklas ; Harbst, Katja ; Rantala, Johanna ; Melin, Beatrice ; Huo, Dezheng ; Olopade, Olufunmilayo I ; Seldon, Joyce ; Ganz, Patricia A ; Nussbaum, Robert L ; Chan, Salina B ; Odunsi, Kunle ; Gayther, Simon A ; Domchek, Susan M ; Arun, Banu K ; Lu, Karen H ; Mitchell, Gillian ; Karlan, Beth Y ; Walsh, Christine ; Lester, Jenny ; Godwin, Andrew K ; Pathak, Harsh ; Ross, Eric ; Daly, Mary B ; Whittemore, Alice S ; John, Esther M ; Miron, Alexander ; Terry, Mary Beth ; Ejlertsen, Bent ; Gerdes, Anne-Marie ; Hansen, Thomas v O ; CIMBA Consortium. / Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. In: J A M A: The Journal of the American Medical Association. 2015 ; Vol. 313, No. 13. pp. 1347-61.

Bibtex

@article{d2282c0edf7547d3b262c29c33c449fc,
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 Bent Ejlertsen and Anne-Marie Gerdes and Hansen, {Thomas v O} and {CIMBA Consortium}",
year = "2015",
month = "4",
day = "7",
doi = "10.1001/jama.2014.5985",
language = "English",
volume = "313",
pages = "1347--61",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "13",

}

RIS

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 - Ejlertsen, Bent

AU - Gerdes, Anne-Marie

AU - Hansen, Thomas v O

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

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 -

ID: 45843882