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Cancer Epidemiol Biomarkers Prev. 2015 Jan;24(1):308-16. doi: 10.1158/1055-9965.EPI-14-0532. Epub 2014 Oct 21.

Candidate genetic modifiers for breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers.

Peterlongo P1, Chang-Claude J2, Moysich KB3, Rudolph A2, Schmutzler RK4, Simard J5, Soucy P5, Eeles RA6, Easton DF7, Hamann U8, Wilkening S9, Chen B10, Rookus MA11, Schmidt MK12, van der Baan FH11, Spurdle AB13, Walker LC14, Lose F13, Maia AT15, Montagna M16, Matricardi L16, Lubinski J17, Jakubowska A17, Gómez Garcia EB18, Olopade OI19, Nussbaum RL20, Nathanson KL21, Domchek SM21, Rebbeck TR22, Arun BK23, Karlan BY24, Orsulic S24, Lester J24, Chung WK25, Miron A26, Southey MC27, Goldgar DE28, Buys SS29, Janavicius R30, Dorfling CM31, van Rensburg EJ31, Ding YC32, Neuhausen SL32, Hansen TV33, Gerdes AM34, Ejlertsen B35, Jønson L33, Osorio A36, Martínez-Bouzas C37, Benitez J38, Conway EE39, Blazer KR40, Weitzel JN41, Manoukian S42, Peissel B42, Zaffaroni D42, Scuvera G42, Barile M43, Ficarazzi F44, Mariette F44, Fortuzzi S44, Viel A45, Giannini G46, Papi L47, Martayan A48, Tibiletti MG49, Radice P50, Vratimos A51, Fostira F51, Garber JE52, Donaldson A53, Brewer C54, Foo C55, Evans DG56, Frost D7, Eccles D57, Brady A58, Cook J59, Tischkowitz M60, Adlard J61, Barwell J62, Walker L63, Izatt L64, Side LE65, Kennedy MJ66, Rogers MT67, Porteous ME68, Morrison PJ69, Platte R7, Davidson R70, Hodgson SV71, Ellis S7, Cole T72; EMBRACE, Godwin AK73, Claes K74, Van Maerken T74, Meindl A75, Gehrig A76, Sutter C77, Engel C78, Niederacher D79, Steinemann D80, Plendl H81, Kast K82, Rhiem K83, Ditsch N84, Arnold N85, Varon-Mateeva R86, Wappenschmidt B83, Wang-Gohrke S87, Bressac-de Paillerets B88, Buecher B89, Delnatte C90, Houdayer C91, Stoppa-Lyonnet D92, Damiola F93, Coupier I94, Barjhoux L95, Venat-Bouvet L96, Golmard L89, Boutry-Kryza N97, Sinilnikova OM98, Caron O99, Pujol P100, Mazoyer S93, Belotti M89; GEMO Study Collaborators, Piedmonte M101, Friedlander ML102, Rodriguez GC103, Copeland LJ104, de la Hoya M105, Segura PP106, Nevanlinna H107, Aittomäki K108, van Os TA109, Meijers-Heijboer HE110, van der Hout AH111, Vreeswijk MP112, Hoogerbrugge N113, Ausems MG114, van Doorn HC115, Collée JM116; HEBON, Olah E117, Diez O118, Blanco I119, Lazaro C120, Brunet J121, Feliubadalo L122, Cybulski C17, Gronwald J17, Durda K17, Jaworska-Bieniek K17, Sukiennicki G17, Arason A123, Chiquette J124, Teixeira MR125, Olswold C126, Couch FJ127, Lindor NM128, Wang X129, Szabo CI130, Offit K131, Corines M132, Jacobs L132, Robson ME131, Zhang L133, Joseph V131, Berger A134, Singer CF134, Rappaport C134, Kaulich DG134, Pfeiler G134, Tea MK134, Phelan CM135, Greene MH136, Mai PL136, Rennert G137, Mulligan AM138, Glendon G139, Tchatchou S140, Andrulis IL141, Toland AE142, Bojesen A143, Pedersen IS144, Thomassen M145, Jensen UB146, Laitman Y147, Rantala J148, von Wachenfeldt A149, Ehrencrona H150, Askmalm MS151, Borg Å152, Kuchenbaecker KB7, McGuffog L7, Barrowdale D7, Healey S13, Lee A7, Pharoah PD153, Chenevix-Trench G13; KConFab Investigators, Antoniou AC7, Friedman E154.

Author information

1
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy. paolo.peterlongo@ifom.eu eitan.friedman@sheba.health.gov.il feitan@post.tau.ac.il.
2
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, New York.
4
Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Germany. Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany, on behalf of the German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC).
5
Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Canada.
6
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, United Kingdom.
7
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
8
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
9
Genomic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
10
Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
11
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
12
Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands.
13
Department of Genetics and Computational Biology, QIMR Berghofer, Brisbane, Australia.
14
Department of Pathology, University of Otago, Christchurch, New Zealand.
15
Department of Biomedical Sciences and Medicine, Gambelas Campus, University of Algarve, Portugal.
16
Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy.
17
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
18
Department of Clinical Genetics, MUMC, Maastricht, the Netherlands.
19
Center for Clinical Cancer Genetics, Department of Medicine and Human Genetics, University of Chicago Medical Center, Chicago, Illinois.
20
Department of Medicine and Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
21
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadephia, Pennsylvania.
22
Department of Epidemiology and Biostatistics, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadephia, Pennsylvania.
23
University of Texas MD Anderson Cancer Center, Houston, Texas.
24
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
25
Departments of Pediatrics and Medicine, Columbia University, New York, New York.
26
Department of Genetics and Genomics at Case Western Reserve Medical School, Cleveland, Ohio.
27
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia.
28
Department of Dermatology, University of Utah School of Medicine, Salt Lake City, Utah.
29
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
30
Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology, and Transfusion Medicine Center, Dept. of Molecular and Regenerative Medicine; State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
31
Department of Genetics, University of Pretoria, Pretoria, South Africa.
32
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California.
33
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
34
Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
35
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
36
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
37
Molecular Genetics Laboratory, Department of Biochemistry, Cruces Hospital Barakaldo, 48903-Barakaldo-Bizkaia, Spain.
38
Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain. Human Genetics Group and Genotyping Unit, Spanish National Cancer Centre (CNIO), Madrid, Spain.
39
Saint Alphonsus Regional Medical Center, care of City of Hope Clinical Cancer Genetics Community Research Network, Duarte, California.
40
Clinical Cancer Genetics, City of Hope, Duarte, California.
41
Clinical Cancer Genetics, City of Hope, Duarte, California (for the City of Hope Clinical Cancer Genetics Community Research Network).
42
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.
43
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
44
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy. Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
45
Division of Experimental Oncology 1, CRO Aviano National Cancer Institute, Aviano (PN), Italy.
46
Department of Molecular Medicine, Sapienza University, Rome, Italy.
47
Unit of Medical Genetics, Department of Biomedical, Experimental, and Clinical Sciences, University of Florence, Florence, Italy.
48
Unit of Genetic Counseling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena, Rome, Italy.
49
UO Anatomia Patologica Ospedale di Circolo e Fondazione Macchi, Polo Universitario Varese, Italy.
50
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.
51
Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Aghia Paraskevi Attikis, Athens, Greece.
52
Dana-Farber Cancer Institute, Boston, Massachuestts.
53
Clinical Genetics Department, St. Michael's Hospital, Bristol, United Kingdom.
54
Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom.
55
Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom.
56
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
57
University of Southampton, Faculty of Medicine, Southampton University Hospitals NHS Trust, Southampton, United Kingdom.
58
North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, United Kingdom.
59
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
60
Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom.
61
Yorkshire Regional Genetics Service, Leeds, United Kingdom.
62
Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, United Kingdom.
63
Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom.
64
Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
65
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
66
Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin, Ireland. St. James's Hospital, Dublin, Ireland.
67
All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, United Kingdom.
68
South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom.
69
Centre for Cancer Research and Cell Biology, Queens University of Belfast, Department of Medical Genetics, Belfast HSC Trust, Belfast, United Kingdom.
70
West of Scotland Regional Genetics Service, Southern General Hospital, Glasgow, United Kingdom.
71
Medical Genetics Unit, St. George's, University of London, London, United Kingdom.
72
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.
73
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Missouri.
74
Center for Medical Genetics, Ghent University, Ghent, Belgium.
75
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Germany.
76
Institute of Human Genetics, University Würzburg, Wurzburg, Germany.
77
University Heidelberg, Heidelberg, Germany.
78
Institute for Medical Informatics, Statistics, and Epidemiology, University of Leipzig, Leipzig, Germany.
79
University Düsseldorf, Dusseldorf, Germany.
80
Hannover Medical School, Hanover, Germany.
81
Institute of Human Genetics, University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany.
82
Department of Gynecology and Obstetrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
83
Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Germany. Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany.
84
Department of Gynaecology and Obstetrics, University Munich, Munich, Germany.
85
Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein/University Kiel, Kiel, Germany.
86
Institute of Human Genetics, Charite Berlin, Germany.
87
Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany.
88
INSERM U946, Fondation Jean Dausset, Paris, France. Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France.
89
Institut Curie, Department of Tumour Biology, Paris, France.
90
Centre René Gauducheau, Nantes, France.
91
Institut Curie, Department of Tumour Biology, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, France.
92
Institut Curie, Department of Tumour Biology, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, France. Institut Curie, INSERM U830, Paris, France.
93
INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
94
Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France. Unité d'Oncogénétique, CRLCC Val d'Aurelle, Montpellier, France.
95
Unité d'Oncogénétique, CRLCC Val d'Aurelle, Montpellier, France.
96
Department of Medical Oncology, Centre Hospitalier Universitaire Dupuytren, Limoges, France.
97
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France.
98
INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France. Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
99
Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France.
100
Unité d'Oncogénétique, CHU Arnaud de Villeneuve, Montpellier, France. INSERM 896, CRCM Val d'Aurelle, Montpellier, France.
101
Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York.
102
Australia New Zealand Gynaecological Oncology Group (ANZGOG), Coordinating Centre, Camperdown, Australia.
103
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois.
104
Ohio State University, Department of Obstetrics and Gynecology, Hilliard, Ohio.
105
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
106
Department of Oncology, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
107
Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki, Finland. University of Helsinki, Helsinki, Finland.
108
Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
109
Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands.
110
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands.
111
Department of Genetics, University Medical Center, Groningen University, Groningen, the Netherlands.
112
Department of Human Genetics, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
113
Department of Human Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
114
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
115
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Erasmus University MC Cancer Institute, Rotterdam, the Netherlands.
116
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands.
117
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
118
Oncogenetics Group, University Hospital Vall d'Hebron, Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain. Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d'Hebron Research Institute (VHIR), Barcelona, Spain.
119
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
120
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
121
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI-Catalan Institute of Oncology, Girona, Spain.
122
BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
123
BMC, Faculty of Medicine, University of Iceland, Reykjavik, Iceland. Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
124
Unité de Recherche en Santé des Populations, Centre des Maladies du Sein Deschênes-Fabia, Centre de Recherche FRSQ du Centre Hospitalier Affilié Universitaire de Québec, Québec, Canada.
125
Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal. Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
126
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnessotta.
127
Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, Minnessotta.
128
Health Sciences Research, Mayo Clinic, Scottsdale, Arizona.
129
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnessotta.
130
National Human Genome Research Institute, NIH, Bethesda, Maryland.
131
Clinical Genetics Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York.
132
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
133
Diagnostic Molecular Genetics Laboratory, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
134
Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
135
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida.
136
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, Maryland.
137
Clalit National Cancer Control Center, Haifa, Israel.
138
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
139
Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
140
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
141
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
142
Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
143
Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
144
Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
145
Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark.
146
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
147
Sheba Medical Center, Tel Aviv, Israel.
148
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
149
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
150
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden. Department of Immunology, Genetics, and Pathology, Uppsala University, Uppsala, Sweden.
151
Division of Clinical Genetics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
152
Department of Oncology, Lund University, Lund, Sweden.
153
Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
154
Sheba Medical Center, Tel Aviv, Israel. paolo.peterlongo@ifom.eu eitan.friedman@sheba.health.gov.il feitan@post.tau.ac.il.

Abstract

BACKGROUND:

BRCA1 and BRCA2 mutation carriers are at substantially increased risk for developing breast and ovarian cancer. The incomplete penetrance coupled with the variable age at diagnosis in carriers of the same mutation suggests the existence of genetic and nongenetic modifying factors. In this study, we evaluated the putative role of variants in many candidate modifier genes.

METHODS:

Genotyping data from 15,252 BRCA1 and 8,211 BRCA2 mutation carriers, for known variants (n = 3,248) located within or around 445 candidate genes, were available through the iCOGS custom-designed array. Breast and ovarian cancer association analysis was performed within a retrospective cohort approach.

RESULTS:

The observed P values of association ranged between 0.005 and 1.000. None of the variants was significantly associated with breast or ovarian cancer risk in either BRCA1 or BRCA2 mutation carriers, after multiple testing adjustments.

CONCLUSION:

There is little evidence that any of the evaluated candidate variants act as modifiers of breast and/or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.

IMPACT:

Genome-wide association studies have been more successful at identifying genetic modifiers of BRCA1/2 penetrance than candidate gene studies.

PMID:
25336561
PMCID:
PMC4294951
DOI:
10.1158/1055-9965.EPI-14-0532
[Indexed for MEDLINE]
Free PMC Article

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