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

The 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

The CIMBA Consortium

Institute of Human Genetics

University of Pennsylvania
Centre Léon Bérard
University of Cambridge
Sheba Medical Center at Tel Hashomer
The Gertner Institute
Rebecca Sieff Government Hospital
Lund University
Uppsala University
Linköping University
Sahlgrenska University Hospital
Karolinska Institutet
Umeå University
The University of Chicago
University of California at Los Angeles
University of California at San Francisco
Roswell Park Cancer Institute
Keck School of Medicine of USC
University of Pennsylvania Health System
MD Anderson Cancer Center
Peter Maccallum Cancer Centre
University of Melbourne
Cedars-Sinai Medical Center
University of Kansas
Fox Chase Cancer Center
Stanford University School of Medicine
Cancer Prevention Institute of California
Dana-Farber Cancer Institute
Columbia University
University of Utah School of Medicine
Huntsman Cancer Institute
German Cancer Research Center
Vilnius University
Latvian Biomedical Research and Study Centre
Beth Israel Deaconess Medical Center
University of Pretoria
City of Hope National Med Center
Rigshospitalet
Iberoamerican Cochrane Centre - Biomedical Research Institute Sant Pau (IIB Sant Pau)
Centro de Investigación en Red de Enfermedades Raras
Lozano Blesa University Clinic Hospital
Hospital Universitario Cruces
Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA)
IRCCS Istituti fisioterapici ospitalieri - Istituto Regina Elena
University of Turin
IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano
European Institute of Oncology
Azienda Ospedaliera - Universitaria Città della Salute e della Scienza di Torino
University of Rome La Sapienza
Cogentech Cancer Genetic Test Laboratory
Università Cattolica del Sacro Cuore, Campus di Roma
FIRC Institute of Molecular Oncology
IRCCS Centro di Riferimento Oncologico - Aviano PN
Liguria Cancer Registry c/o IST/UNIGE
Demokritos National Centre for Scientific Research
Shaukat Khanum Memorial Cancer Hospital and Research Centre
Manchester University NHS Foundation Trust
Institute of Cancer Research
NHS Greater Glasgow and Clyde
University Hospital Southampton NHS Foundation Trust
Birmingham Women's and Children's NHS Foundation Trust
Sheffield Children's NHS Foundation Trust
Royal Devon & Exeter NHS Foundation Trust
University of London
Belfast Health and Social Care Trust
Oxford University Hospitals NHS Foundation Trust
NHS Lothian
St James's Hospital
Guy’s Hospital
Yorkshire Regional Genetics Service
SouthWest Regional Genetics Service
University of Cologne
Leipzig University
Klinikum Rechts der Isar
University Medical Center Schleswig-Holstein
University Hospital Düsseldorf
Heidelberg University
Ulm University
Hannover Medical School
Technische Universität Dresden
Charité Universitätsmedizin
University of Würzburg
University of Regensburg
Institut Curie
INSERM U830
Université Paris Cité
Centre de Recherche en Cancérologie de Lyon
Hospices Civils de LyonCentre Léon Bérard
Universite Claude Bernard Lyon 1
Aix-Marseille Université
Centre Oscar Lambret
CLCC Paul Strauss
Université de Franche-Comté
Centre Hospitalier Universitaire Bretonneau
Georgetown University
Ghent University Hospital
GOG Statistical and Data Center
Evanston Hospital
Friedman School of Nutrition Science and Policy
University of North Carolina
New York University
Good Samaritan Hospital
Yale University
Hospital Clinico San Carlos
University of Helsinki
Helsinki University Hospital
University of Groningen
Netherlands Cancer Institute
Erasmus University Rotterdam
VU University Medical Center Amsterdam
Leiden University
Maastricht University
Radboud University Nijmegen
Utrecht University
Amsterdam University Medical Centers
Hong Kong Hereditary Breast Cancer Family Registry
Hong Kong Sanatorium & Hospital
The University of Hong Kong
National Institute of Oncology
Autonomous University of Barcelona
Vall d’Hebron Hospital
Institute Catala Oncologia
Pomeranian Medical University in Szczecin
Medical University of Warsaw
Department of Pathology
University of Iceland
Research Center
Université Laval
Université Laval Research Center
IRCCS Istituto Oncologico Veneto - Padova
North Region Cancer Registry, Portuguese Oncology Institute
University of Porto
Queensland Institute of Medical Research
Soonchunhyang University
Seoul National University
The Catholic University of Korea
Mayo Clinic Rochester, MN
McGill University
Masaryk Memorial Cancer Institute
Memorial Sloan-Kettering Cancer Center
Medical University of Vienna
National Cancer Institute (NCI)
N.N. Petrov Institute of Oncology
Ohio State University
University of Southern Denmark
Aalborg University
Aarhus University
Odense University Hospital
University of Pisa
Sime Darby Medical Centre
University of Malaya
NorthShore University HealthSystem
University of Toronto

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

457 Scopus citations

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
Number of pages	15
Journal	JAMA - Journal of the American Medical Association
Volume	313
Issue number	13
DOIs	https://doi.org/10.1001/jama.2014.5985
State	Published - 07 Apr 2015

UN SDGs

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

SDG 3 Good Health and Well-being

Access to Document

10.1001/jama.2014.5985

Cite this

@article{e46c9dc636c0494ca3fffb2425e3336e,

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 = "\{The CIMBA Consortium\} and 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 Diana Torres",

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 = "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 - The CIMBA Consortium

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 - Torres, Diana

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.

UR - https://www.scopus.com/pages/publications/84927556016

U2 - 10.1001/jama.2014.5985

DO - 10.1001/jama.2014.5985

M3 - Article

C2 - 25849179

AN - SCOPUS:84927556016

SN - 0098-7484

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

Other files and links

Fingerprint

Cite this