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PLoS One. 2016 Jul 27;11(7):e0158801. doi: 10.1371/journal.pone.0158801. eCollection 2016.

Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Vigorito E1, Kuchenbaecker KB1, Beesley J2, Adlard J3, Agnarsson BA4, Andrulis IL5, Arun BK6, Barjhoux L7, Belotti M8, Benitez J9, Berger A10, Bojesen A11, Bonanni B12, Brewer C13, Caldes T14, Caligo MA15, Campbell I16, Chan SB17, Claes KB18, Cohn DE19, Cook J20, Daly MB21, Damiola F7, Davidson R22, Pauw Ad8, Delnatte C23, Diez O24, Domchek SM25, Dumont M26, Durda K27, Dworniczak B28, Easton DF1, Eccles D29, Edwinsdotter Ardnor C30, Eeles R31, Ejlertsen B32, Ellis S33, Evans DG34, Feliubadalo L35, Fostira F36, Foulkes WD37, Friedman E38, Frost D33, Gaddam P39, Ganz PA40, Garber J41, Garcia-Barberan V14, Gauthier-Villars M8, Gehrig A42, Gerdes AM43, Giraud S44, Godwin AK45, Goldgar DE46, Hake CR47, Hansen TV48, Healey S2, Hodgson S49, Hogervorst FB50, Houdayer C8, Hulick PJ51, Imyanitov EN52, Isaacs C53, Izatt L54, Izquierdo A55, Jacobs L56, Jakubowska A27, Janavicius R57, Jaworska-Bieniek K27, Jensen UB58, John EM59, Vijai J60, Karlan BY61, Kast K62, Investigators K63, Khan S64, Kwong A65, Laitman Y66, Lester J61, Lesueur F67, Liljegren A68, Lubinski J27, Mai PL69, Manoukian S70, Mazoyer S7, Meindl A71, Mensenkamp AR72, Montagna M73, Nathanson KL25, Neuhausen SL74, Nevanlinna H64, Niederacher D75, Olah E76, Olopade OI77, Ong KR78, Osorio A79, Park SK80, Paulsson-Karlsson Y81, Pedersen IS82, Peissel B70, Peterlongo P83, Pfeiler G84, Phelan CM85, Piedmonte M86, Poppe B18, Pujana MA87, Radice P88, Rennert G89, Rodriguez GC90, Rookus MA91, Ross EA92, Schmutzler RK93, Simard J26, Singer CF94, Slavin TP95, Soucy P26, Southey M96, Steinemann D97, Stoppa-Lyonnet D8, Sukiennicki G27, Sutter C98, Szabo CI99, Tea MK94, Teixeira MR100, Teo SH101, Terry MB102, Thomassen M103, Tibiletti MG104, Tihomirova L105, Tognazzo S73, van Rensburg EJ106, Varesco L107, Varon-Mateeva R108, Vratimos A109, Weitzel JN95, McGuffog L1, Kirk J110, Toland AE111, Hamann U112, Lindor N113, Ramus SJ114, Greene MH69, Couch FJ115, Offit K116, Pharoah PD117, Chenevix-Trench G2, Antoniou AC1.

Author information

1
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
2
Department of Genetics, QIMR Berghofer Medical Research Institute, Herston Road, Brisbane, Australia, 4029.
3
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, United Kingdom.
4
Department of Pathology, University Hospital (Landspitali) and University of Iceland School of Medicine, Hringbraut, 101 Reykjavik, Iceland.
5
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
6
Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX, United States of America.
7
Bâtiment Cheney D, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
8
Service de Génétique Oncologique, Institut Curie, 26, rue d'Ulm, Paris Cedex 05, France.
9
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain, and Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
10
Dept of OB/GYN, Medical University of Vienna, Vienna, Austria.
11
Department of Clinical Genetics, Vejle Hospital, Kabbeltoft 25, Vejle, Denmark.
12
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), via Ripamonti 435, 20141 Milan, Italy.
13
Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom.
14
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
15
Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Pisa Italy.
16
Research Division, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, VIC 8006, Australia.
17
1600 Divisadero Street, C415, San Francisco, CA 94143-1714, United States of America.
18
Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000 Gent, Belgium.
19
Ohio State University Columbus Cancer Council GYN Oncology, 3651 Ridge Mill Drive, Columbus, OH 43026, United States of America.
20
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
21
Department of Clinical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, United States of America.
22
Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, United Kingdom.
23
Unité d'oncogénétique, ICO-Centre René Gauducheau, Boulevard Jacques Monod, 44805 Nantes Saint Herblain Cedex, France.
24
Oncogenetics Group, Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), and Universitat Autònoma, Passeig Vall d'Hebron 119-129, Barcelona, Spain.
25
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, 3400 Civic Center Boulevard, Philadelphia, PA 19104, United States of America.
26
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City (Quebec), Canada.
27
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
28
Institute of Human Genetics, University of Münster, Münster, Germany.
29
University of Southampton Faculty of Medicine, Southampton University Hospitals NHS Trust, Southampton, United Kingdom.
30
Department of Radiation Sciences, Oncology, Umeå University, Umea, Sweden.
31
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.
32
Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
33
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, United Kingdom.
34
Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
35
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, 08908 L'Hospitalet, Barcelona, Spain.
36
Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos", Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi, Attiki, Athens, Greece.
37
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada.
38
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan 52621, and Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
39
Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY, United States of America.
40
UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA 90095-6900, United States of America.
41
Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, United States of America.
42
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany.
43
Department of Clinical Genetics, Rigshospitalet 4062, Blegdamsvej 9, København Ø, Denmark.
44
Service de Génétique Moléculaire et Clinique, Hospices Civils de Lyon, Lyon cedex 04, France.
45
Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS 3040, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
46
Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT 84132, United States of America.
47
City of Hope Clinical Cancer Genetics Community Research Network, 1500 East Duarte Road, Duarte, CA 91010, United States of America.
48
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
49
Medical Genetics Unit, St George's, University of London, London, United Kingdom.
50
Family Cancer Clinic, Netherlands Cancer Institute, P.O. Box 90203, 1000 BE, Amsterdam, The Netherlands.
51
Center for Medical Genetics, NorthShore University Health System, University of Chicago Pritzker School of Medicine, 1000 Central Street, Suite 620, Evanston, IL 60201, United States of America.
52
N.N. Petrov Institute of Oncology, St.-Petersburg 197758, Russia.
53
Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, United States of America.
54
Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
55
Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, Av. França s/n. 1707 Girona, Spain.
56
Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, United States of America.
57
Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine, Santariskiu st., State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania.
58
Department of Clinical Genetics, Aarhus University Hospital, Brendstrupgaardsvej 21C, Aarhus N, Denmark.
59
Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, United States of America.
60
Clinical Genetics Research Laboratory, Dept. of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10044, United States of America.
61
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, United States of America.
62
Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
63
Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia.
64
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700 (Haartmaninkatu 8), 00029 HUS, Finland.
65
The Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong China.
66
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan 52621, Israel.
67
Genetic Epidemiology of Cancer team, Inserm U900, Institut Curie, Mines ParisTech, 26 rue d'Ulm, 75248 Paris cedex 05, France.
68
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
69
Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, United States of America.
70
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133 Milan, Italy.
71
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
72
Department of Human Genetics, Radboud university medical centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
73
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Via Gattamelata 64, Padua, Italy.
74
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, United States of America.
75
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
76
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
77
The University of Chicago Medicine, 5841 South Maryland Avenue, MC 2115 Chicago, IL 60637.
78
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.
79
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
80
Department of Preventive Medicine, Seoul National University College of Medicine, Department of Biomedical Science, Seoul National University Graduate School, and Cancer Research Institute, Seoul National University, 103 Daehak-ro, Jongno-gu, Seoul 110-799, Korea.
81
Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
82
Section of Molecular Diagnostics, Department of Biochemistry, Aalborg University Hospital, Reberbansgade 15, Aalborg, Denmark.
83
IFOM, The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, c/o IFOM-IEO campus, via Adamello 16, 20139 Milan, Italy.
84
Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
85
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
86
NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY 14263, United States of America.
87
Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, Barcelona, Spain.
88
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133 Milan, Italy.
89
Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, 7 Michal St., Haifa 34362, Israel.
90
Division of Gynecologic Oncology, NorthShore University HealthSystem, Univ of Chicago, 2650 Ridge Avenue Suite 1507 Walgreens, Evanston, IL 60201, United States of America.
91
Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000 BE, Amsterdam, The Netherlands.
92
Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States of America.
93
Center for Hereditary Breast and Ovarian Cancer, Medical Faculty, University Hospital Cologne, Cologne, Germany.
94
Dept of OB/GYN, Medical University of Vienna, Vienna, Austria, and Waehringer Guertel 18-20, A 1090 Vienna, Austria.
95
Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California 91010, United States of America.
96
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
97
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
98
Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
99
National Human Genome Research Institute, National Institutes of Health, Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD 20892-8004, United States of America.
100
Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
101
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500 Malaysia.
102
Department of Epidemiology, Columbia University, New York, NY, United States of America.
103
Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
104
UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Via O.Rossi 9, 21100 Varese, Italy.
105
Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia.
106
Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa.
107
Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, largo Rosanna Benzi 10, 16132 Genoa, Italy.
108
Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany.
109
Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos" Patriarchou Gregoriou & Neapoleos str., Aghia Paraskevi, Attiki, Athens, Greece.
110
Westmead Hospital, Familial Cancer Service, Hawkesbury Road, P.O. Box 533, Wentworthville, NSW 2145, Australia.
111
Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH, United States of America.
112
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
113
Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ, United States of America.
114
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, California, United States of America.
115
Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, United States of America.
116
Clinical Genetics Research Laboratory, Dept. of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10044, United States of America.
117
Department of Oncology, University of Cambridge, Cambridge, United Kingdom.

Abstract

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

PMID:
27463617
PMCID:
PMC4963094
DOI:
10.1371/journal.pone.0158801
[Indexed for MEDLINE]
Free PMC Article

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