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

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

CIMBA Consortium

Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia2Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
Centre de Recherche en Cancérologie de Lyon, UMR Inserm, Centre Léon Bérard, Lyon, France.
Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia6Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.
Department of Gynecology, Sheba Medical Center, Ramat Gan, Israel and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
Department of Oncology, Ella Institute for Melanoma, Sheba Medical Center, Derech Sheba 2, Tel-Hashomer, Ramat-Gan, Israel. Electronic address: [email protected].
Oncology Institute, Rivkah Ziv Medical Center Zefat, Israel.
Department of Oncology, Lund University, Lund, Sweden12Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. [email protected].
Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden.
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois.
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, California.
Department of Medicine and Genetics, University of California, San Francisco, San Francisco, CA, USA. [email protected].
Cancer Risk Program, Helen Diller Family Cancer Center, University of California, San Francisco.
Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, New York.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA. [email protected].
Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Division of Cancer Medicine, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia 25Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS.
Fox Chase Cancer Center, Philadelphia, Pennsylvania.
*Division of Sports Medicine, Department of Orthopaedic Surgery, Stanford University School of Medicine, Stanford, California; †Department of Orthopaedic Surgery, Human Performance Laboratory, Stanford University School of Medicine, Stanford, California; ‡Department of Healthy Policy and Management, Harvard University, Boston, Massachusetts...
Department of Epidemiology, Cancer Prevention Institute of California, Fremont.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm; Department of Pediatrics, Örebro University Hospital, Örebro, Sweden; Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK; Department of Medicine, Celiac Disease Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.

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

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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
Pages (from-to)	1347-61
Number of pages	15
Journal	JAMA
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)

SDG 3 Good Health and Well-being

Keywords

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

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10.1001/jama.2014.5985

Association-of-type-and-location-of-brca1-and-brca2-mutations-with-risk-of-breast-and-ovarian-cancer.pdfFinal published version, 525 KBLicence: Taverne

Cite this

@article{8d3c441685434132bc54d80409dd1618,

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/genetics, Female, Genes, BRCA1, Genes, BRCA2, Genetic Predisposition to Disease, Heterozygote, Humans, Middle Aged, Mutation, Nucleotides, Ovarian Neoplasms/genetics, Risk Factors",

author = "\{CIMBA Consortium\} and 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 Coll{\'e}e, \{J Margriet\} and Oosterwijk, \{Jan C\} and Aalfs, \{Cora M\}",

year = "2015",

month = apr,

day = "7",

doi = "10.1001/jama.2014.5985",

language = "English",

volume = "313",

pages = "1347--61",

journal = "JAMA",

issn = "0098-7484",

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 - CIMBA Consortium

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 - Collée, J Margriet

AU - Oosterwijk, Jan C

AU - Aalfs, Cora M

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/genetics

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/genetics

KW - Risk Factors

U2 - 10.1001/jama.2014.5985

DO - 10.1001/jama.2014.5985

M3 - Article

SN - 0098-7484

VL - 313

SP - 1347

EP - 1361

JO - JAMA

JF - JAMA

IS - 13

ER -

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

Abstract

UN SDGs

Keywords

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