Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.
David G Cox
(1)
,
Jacques Simard
(2)
,
Daniel Sinnett
(3, 4)
,
Yosr Hamdi
,
Penny Soucy
(2)
,
Manon Ouimet
,
Laure Barjhoux
(1)
,
Carole Verny-Pierre
(1)
,
Lesley Mcguffog
(5)
,
Sue Healey
(6)
,
Csilla Szabo
(7)
,
Mark H Greene
(8)
,
Phuong L Mai
,
Irene L Andrulis
,
Mads Thomassen
(9)
,
Anne-Marie Gerdes
(10)
,
Maria A Caligo
,
Eitan Friedman
(11, 12)
,
Yael Laitman
(12)
,
Bella Kaufman
(12)
,
Shani S Paluch
,
Åke Borg
(13)
,
Per Karlsson
(14)
,
Marie Stenmark Askmalm
,
Gisela Barbany Bustinza
,
Katherine L Nathanson
(15)
,
Susan M Domchek
,
Timothy R Rebbeck
,
Javier Benítez
(16, 17)
,
Ute Hamann
(18)
,
Matti A Rookus
,
Ans M W van den Ouweland
,
Margreet G E M Ausems
,
Cora M Aalfs
,
Christi J van Asperen
,
Peter Devilee
(19)
,
Hans J J P Gille
,
Susan Peock
(5)
,
Debra Frost
(5)
,
D Gareth Evans
(20)
,
Ros Eeles
(21)
,
Louise Izatt
(22)
,
Julian Adlard
(23)
,
Joan Paterson
(24)
,
Jacqueline Eason
(25)
,
Andrew K Godwin
,
Marie-Alice Remon
(26)
,
Virginie Moncoutier
,
Marion Gauthier-Villars
(27)
,
Christine Lasset
(28, 29)
,
Sophie Giraud
(30)
,
Agnès Hardouin
(31)
,
Pascaline Berthet
(32)
,
Hagay Sobol
(33, 34)
,
François Eisinger
(35)
,
Brigitte Bressac de Paillerets
,
Olivier Caron
(36)
,
Capucine Delnatte
(37)
,
David Goldgar
(38)
,
Alex Miron
,
Hilmi Ozcelik
(39, 40)
,
Saundra Buys
(41)
,
Melissa C Southey
,
Mary Beth Terry
,
Christian F Singer
,
Anne-Catharina Dressler
(42)
,
Muy-Kheng Tea
(43)
,
Thomas V O Hansen
,
Oskar Johannsson
(44, 45)
,
Marion Piedmonte
(46)
,
Gustavo C Rodriguez
,
Jack B Basil
,
Stephanie Blank
,
Amanda E Toland
,
Marco Montagna
(47)
,
Claudine Isaacs
(48)
,
Ignacio Blanco
(49)
,
Simon A Gayther
,
Kirsten B Moysich
,
Rita K Schmutzler
,
Barbara Wappenschmidt
(50)
,
Christoph Engel
(51)
,
Alfons Meindl
(52)
,
Nina Ditsch
(53)
,
Norbert Arnold
(54)
,
Dieter Niederacher
(55)
,
Christian Sutter
(56)
,
Dorothea Gadzicki
(57)
,
Britta Fiebig
(58)
,
Trinidad Caldes
(59)
,
Rachel Laframboise
,
Heli Nevanlinna
(60)
,
Xiaoqing Chen
(6)
,
Jonathan Beesley
(6)
,
Amanda B Spurdle
,
Susan L Neuhausen
,
Yuan C Ding
,
Fergus J Couch
,
Xianshu Wang
(61)
,
Paolo Peterlongo
(62)
,
Siranoush Manoukian
(63)
,
Loris Bernard
(64)
,
Paolo Radice
(62)
,
Douglas F Easton
(65, 66)
,
Georgia Chenevix-Trench
(6)
,
Antonis C Antoniou
,
Dominique Stoppa-Lyonnet
(27, 67)
,
Sylvie Mazoyer
(1)
,
Olga M Sinilnikova
(1)
,
Non Renseigné
1
UNICANCER/CRCL -
Centre de Recherche en Cancérologie de Lyon
2 Cancer Genomics Laboratory
3 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
4 Department of Pediatrics
5 Centre for Cancer Genetic Epidemiology
6 Queensland Institute of Medical Research
7 University of Delaware [Newark]
8 Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics
9 Department of Clinical Genetics
10 Department of Clinical Genetics [Copenhagen]
11 Sackler Faculty of Medicine
12 The Susanne Levy Gertner Oncogenetics Unit
13 Department of Oncology, Clinical Sciences
14 Department of Oncology
15 Depts of Medicine and Biostatistics and Epidemology
16 Human Genetics Group
17 Biomedical Research Centre Network for Rare Diseases
18 Molecular Genetics of Breast Cancer
19 Department of Genetic Epidemiology
20 Genetic Medicine
21 Oncogenetics Team
22 Clinical Genetics
23 Yorkshire Regional Genetics Service
24 Department of Clinical Genetics
25 Nottingham Clinical Genetics Service
26 génétique
27 Service de Génétique Oncologique
28 Biostatistiques santé [LBBE]
29 Equipe de prévention et épidémiologie génétique
30 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
31 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
32 Consultation d'Oncogénétique
33 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
34 Service d'Oncologie Génétique, de Prévention et Dépistage
35 SESSTIM - U912 INSERM - Aix Marseille Univ - IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
36 GO - UMR 8125 - Génétique oncologique
37 Centre René Gauducheau
38 Department of Dermatology
39 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology
40 Samuel Lunenfeld Research Institute
41 Department of Internal Medicine
42 Division of Special Gynecology
43 Dept of OB/GYN and Comprehensive Cancer Center
44 Department of Oncology
45 Faculty of Medicine
46 Statistical and Data Center
47 Immunology and Molecular Oncology Unit
48 Lombardi Comprehensive Cancer Center
49 Genetic Counselling Unit
50 Department of Gynaecology and Obstetrics
51 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
52 Department of Gynaecology and Obstetrics
53 Department of Gynaecology and Obstetrics
54 Department of Gynaecology and Obstetrics
55 Department of Gynaecology and Obstetrics
56 Institute of Human Genetics
57 Institute of Cell and Molecular Pathology
58 Institute of Human Genetics
59 Molecular Oncology Laboratory
60 Department of Obstetrics and Gynecology
61 Department of Laboratory Medicine and Pathology
62 Unit of Molecular Bases of Genetic Risk and Genetic Testing
63 Unit of Medical Genetics
64 Department of Experimental Oncology
65 Cancer Research U.K. Genetic Epidemiology Unit
66 Genetic Epidemiology Unit, Department of Public Health and Primary Care
67 U830 - Unité de génétique et biologie des cancers
2 Cancer Genomics Laboratory
3 Centre de recherche du CHU Sainte-Justine / Research Center of the Sainte-Justine University Hospital [Montreal, Canada]
4 Department of Pediatrics
5 Centre for Cancer Genetic Epidemiology
6 Queensland Institute of Medical Research
7 University of Delaware [Newark]
8 Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics
9 Department of Clinical Genetics
10 Department of Clinical Genetics [Copenhagen]
11 Sackler Faculty of Medicine
12 The Susanne Levy Gertner Oncogenetics Unit
13 Department of Oncology, Clinical Sciences
14 Department of Oncology
15 Depts of Medicine and Biostatistics and Epidemology
16 Human Genetics Group
17 Biomedical Research Centre Network for Rare Diseases
18 Molecular Genetics of Breast Cancer
19 Department of Genetic Epidemiology
20 Genetic Medicine
21 Oncogenetics Team
22 Clinical Genetics
23 Yorkshire Regional Genetics Service
24 Department of Clinical Genetics
25 Nottingham Clinical Genetics Service
26 génétique
27 Service de Génétique Oncologique
28 Biostatistiques santé [LBBE]
29 Equipe de prévention et épidémiologie génétique
30 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
31 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]
32 Consultation d'Oncogénétique
33 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
34 Service d'Oncologie Génétique, de Prévention et Dépistage
35 SESSTIM - U912 INSERM - Aix Marseille Univ - IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale
36 GO - UMR 8125 - Génétique oncologique
37 Centre René Gauducheau
38 Department of Dermatology
39 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology
40 Samuel Lunenfeld Research Institute
41 Department of Internal Medicine
42 Division of Special Gynecology
43 Dept of OB/GYN and Comprehensive Cancer Center
44 Department of Oncology
45 Faculty of Medicine
46 Statistical and Data Center
47 Immunology and Molecular Oncology Unit
48 Lombardi Comprehensive Cancer Center
49 Genetic Counselling Unit
50 Department of Gynaecology and Obstetrics
51 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
52 Department of Gynaecology and Obstetrics
53 Department of Gynaecology and Obstetrics
54 Department of Gynaecology and Obstetrics
55 Department of Gynaecology and Obstetrics
56 Institute of Human Genetics
57 Institute of Cell and Molecular Pathology
58 Institute of Human Genetics
59 Molecular Oncology Laboratory
60 Department of Obstetrics and Gynecology
61 Department of Laboratory Medicine and Pathology
62 Unit of Molecular Bases of Genetic Risk and Genetic Testing
63 Unit of Medical Genetics
64 Department of Experimental Oncology
65 Cancer Research U.K. Genetic Epidemiology Unit
66 Genetic Epidemiology Unit, Department of Public Health and Primary Care
67 U830 - Unité de génétique et biologie des cancers
Jacques Simard
- Fonction : Auteur
- PersonId : 757778
- ORCID : 0000-0001-6906-3390
Yosr Hamdi
- Fonction : Auteur
- PersonId : 767950
- ORCID : 0000-0002-2815-1834
Manon Ouimet
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Phuong L Mai
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Irene L Andrulis
- Fonction : Auteur
Maria A Caligo
- Fonction : Auteur
Shani S Paluch
- Fonction : Auteur
Marie Stenmark Askmalm
- Fonction : Auteur
Gisela Barbany Bustinza
- Fonction : Auteur
Susan M Domchek
- Fonction : Auteur
Timothy R Rebbeck
- Fonction : Auteur
Matti A Rookus
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Ans M W van den Ouweland
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Margreet G E M Ausems
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Cora M Aalfs
- Fonction : Auteur
Christi J van Asperen
- Fonction : Auteur
Peter Devilee
- Fonction : Auteur
- PersonId : 763377
- ORCID : 0000-0002-8023-2009
- IdRef : 074428608
Hans J J P Gille
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Andrew K Godwin
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Virginie Moncoutier
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Sophie Giraud
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- PersonId : 1359982
- ORCID : 0000-0003-1243-3084
Brigitte Bressac de Paillerets
- Fonction : Auteur
Alex Miron
- Fonction : Auteur
Melissa C Southey
- Fonction : Auteur
Mary Beth Terry
- Fonction : Auteur
Christian F Singer
- Fonction : Auteur
Thomas V O Hansen
- Fonction : Auteur
Gustavo C Rodriguez
- Fonction : Auteur
Jack B Basil
- Fonction : Auteur
Stephanie Blank
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Amanda E Toland
- Fonction : Auteur
Simon A Gayther
- Fonction : Auteur
Kirsten B Moysich
- Fonction : Auteur
Rita K Schmutzler
- Fonction : Auteur
Rachel Laframboise
- Fonction : Auteur
Heli Nevanlinna
- Fonction : Auteur
- PersonId : 762552
- ORCID : 0000-0002-0916-2976
Amanda B Spurdle
- Fonction : Auteur
Susan L Neuhausen
- Fonction : Auteur
Yuan C Ding
- Fonction : Auteur
Fergus J Couch
- Fonction : Auteur
Paolo Peterlongo
- Fonction : Auteur
- PersonId : 762723
- ORCID : 0000-0001-6951-6855
Paolo Radice
- Fonction : Auteur
- PersonId : 763238
- ORCID : 0000-0001-6298-4111
Antonis C Antoniou
- Fonction : Auteur
Dominique Stoppa-Lyonnet
- Fonction : Auteur
- PersonId : 770393
- ORCID : 0000-0002-5438-8309
- IdRef : 050298550
Sylvie Mazoyer
- Fonction : Auteur
- PersonId : 752568
- IdHAL : sylvie-mazoyer
- ORCID : 0000-0002-2135-0160
- IdRef : 075600390
Olga M Sinilnikova
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- PersonId : 922678
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Non Renseigné
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Résumé
Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.