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PLoS Genet. 2014 Apr 3;10(4):e1004256. doi: 10.1371/journal.pgen.1004256. eCollection 2014 Apr.

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Osorio A1, Milne RL2, Kuchenbaecker K3, Vaclová T4, Pita G5, Alonso R5, Peterlongo P6, Blanco I7, de la Hoya M8, Duran M9, Díez O10, Ramón Y Cajal T11, Konstantopoulou I12, Martínez-Bouzas C13, Andrés Conejero R14, Soucy P15, McGuffog L3, Barrowdale D3, Lee A3, Swe-Brca16, Arver B17, Rantala J18, Loman N19, Ehrencrona H20, Olopade OI21, Beattie MS22, Domchek SM23, Nathanson K23, Rebbeck TR24, Arun BK25, Karlan BY26, Walsh C26, Lester J26, John EM27, Whittemore AS28, Daly MB29, Southey M30, Hopper J31, Terry MB32, Buys SS33, Janavicius R34, Dorfling CM35, van Rensburg EJ35, Steele L36, Neuhausen SL36, Ding YC36, Hansen TV37, Jønson L37, Ejlertsen B38, Gerdes AM39, Infante M9, Herráez B5, Moreno LT5, Weitzel JN40, Herzog J40, Weeman K40, Manoukian S41, Peissel B41, Zaffaroni D41, Scuvera G41, Bonanni B42, Mariette F43, Volorio S43, Viel A44, Varesco L45, Papi L46, Ottini L47, Tibiletti MG48, Radice P49, Yannoukakos D12, Garber J50, Ellis S3, Frost D3, Platte R3, Fineberg E3, Evans G51, Lalloo F51, Izatt L52, Eeles R53, Adlard J54, Davidson R55, Cole T56, Eccles D57, Cook J58, Hodgson S59, Brewer C60, Tischkowitz M61, Douglas F62, Porteous M63, Side L64, Walker L65, Morrison P66, Donaldson A67, Kennedy J68, Foo C69, Godwin AK70, Schmutzler RK71, Wappenschmidt B71, Rhiem K71, Engel C72, Meindl A73, Ditsch N73, Arnold N74, Plendl HJ75, Niederacher D76, Sutter C77, Wang-Gohrke S78, Steinemann D79, Preisler-Adams S80, Kast K81, Varon-Mateeva R82, Gehrig A83, Stoppa-Lyonnet D84, Sinilnikova OM85, Mazoyer S86, Damiola F86, Poppe B87, Claes K87, Piedmonte M88, Tucker K89, Backes F90, Rodríguez G91, Brewster W92, Wakeley K93, Rutherford T94, Caldés T8, Nevanlinna H95, Aittomäki K95, Rookus MA96, van Os TA97, van der Kolk L98, de Lange JL96, Meijers-Heijboer HE99, van der Hout AH100, van Asperen CJ101, Gómez Garcia EB102, Hoogerbrugge N103, Collée JM104, van Deurzen CH105, van der Luijt RB106, Devilee P107, Hebon108, Olah E109, Lázaro C110, Teulé A7, Menéndez M110, Jakubowska A111, Cybulski C111, Gronwald J111, Lubinski J111, Durda K111, Jaworska-Bieniek K112, Johannsson OT113, Maugard C114, Montagna M115, Tognazzo S115, Teixeira MR116, Healey S117, Investigators K118, Olswold C119, Guidugli L120, Lindor N121, Slager S119, Szabo CI122, Vijai J123, Robson M124, Kauff N124, Zhang L125, Rau-Murthy R124, Fink-Retter A126, Singer CF126, Rappaport C126, Geschwantler Kaulich D126, Pfeiler G126, Tea MK126, Berger A126, Phelan CM127, Greene MH128, Mai PL128, Lejbkowicz F129, Andrulis I130, Mulligan AM131, Glendon G132, Toland AE133, Bojesen A134, Pedersen IS135, Sunde L136, Thomassen M137, Kruse TA137, Jensen UB136, Friedman E138, Laitman Y138, Shimon SP138, Simard J139, Easton DF3, Offit K123, Couch FJ140, Chenevix-Trench G117, Antoniou AC3, Benitez J141.

Author information

1
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
2
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
4
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.
5
Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain.
6
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.
7
Genetic Counseling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
8
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC, Madrid, Spain.
9
Institute of Biology and Molecular Genetics, Universidad de Valladolid (IBGM-UVA), Valladolid, Spain.
10
Oncogenetics Laboratory, University Hospital Vall d'Hebron, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Institut de Recerca (VHIR), and Universitat Autonoma de Barcelona, Barcelona, Spain.
11
Oncology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
12
Molecular Diagnostics Laboratory IRRP, National Centre for Scientific Research Demokritos Aghia Paraskevi Attikis, Athens, Greece.
13
Molecular Genetics Laboratory (Department of Biochemistry), Cruces Hospital Barakaldo, Bizkaia, Spain.
14
Medical Oncology Service, Hospital Clínico Lozano Blesa, San Juan Bosco, Zaragoza, Spain.
15
Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada.
16
Department of Oncology, Lund University, Lund, Sweden.
17
Department of Oncology, Karolinska University Hospital, Stockholm, Sweden.
18
Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
19
Department of Oncology, Lund University Hospital, Lund, Sweden.
20
Department of Clinical Genetics, Lund University Hospital, Lund, Sweden.
21
Center for Clinical Cancer Genetics and Global Health, University of Chicago Medical Center, Chicago, Illinois, United States of America.
22
Departments of Medicine, Epidemiology, and Biostatistics, University of California, San Francisco, San Francisco, California, United States of America.
23
Abramson Cancer Center and Department of Medicine, The University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
24
Abramson Cancer Center and Center for Clinical Epidemiology and Biostatistics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
25
University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
26
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
27
Department of Epidemiology, Cancer Prevention Institute of California, Fremont, California, United States of America.
28
Department of Health Research & Policy, Stanford University School of Medicine, Stanford, California, United States of America.
29
Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America.
30
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Australia.
31
Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Victoria, Australia.
32
Department of Epidemiology, Columbia University, New York, New York, United States of America.
33
Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
34
Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania.
35
Department of Genetics, University of Pretoria, Pretoria, South Africa.
36
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California, United States of America.
37
Center for Genomic Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
38
Department of Oncology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
39
Department of Clinical Genetics, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
40
Clinical Cancer Genetics, City of Hope, Duarte, California, United States of America.
41
Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.
42
Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy.
43
IFOM, Fondazione Istituto FIRC di Oncologia Molecolare and Cogentech Cancer Genetic Test Laboratory, Milan, Italy.
44
Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCCS, Aviano, Italy.
45
Unit of Hereditary Cancer, Department of Epidemiology, Prevention and Special Functions, IRCCS AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
46
Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
47
Department of Molecular Medicine, "Sapienza" University, Rome, Italy.
48
UO Anatomia Patologica, Ospedale di Circolo-Università dell'Insubria, Varese, Italy.
49
Unit of Molecular bases of genetic risk and genetic testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.
50
Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.
51
Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
52
South East Thames Regional Genetics Service, Guy's Hospital London, United Kingdom.
53
Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom.
54
Yorkshire Regional Genetics Service, Leeds, United Kingdom.
55
Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, United Kingdom.
56
West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, United Kingdom.
57
Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom.
58
Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, United Kingdom.
59
Clinical Genetics Department, St Georges Hospital, University of London, London, United Kingdom.
60
Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, United Kingdom.
61
Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, United Kingdom.
62
Institute of Human Genetics, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom.
63
South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, United Kingdom.
64
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, United Kingdom.
65
Oxford Regional Genetics Service, Churchill Hospital, Oxford, United Kingdom.
66
Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, United Kingdom.
67
South West Regional Genetics Service, Bristol, United Kingdom.
68
Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
69
Cheshire & Merseyside Clinical Genetics Service, Liverpool Women's NHS Foundation Trust, Liverpool, United Kingdom.
70
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
71
Centre of Familial Breast and Ovarian Cancer and Centre for Integrated Oncology (CIO), University Hospital of Cologne, Cologne, Germany.
72
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
73
Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
74
Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
75
Institute of Human Genetics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany.
76
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
77
Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
78
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
79
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
80
Institute of Human Genetics, University of Münster, Münster, Germany.
81
Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
82
Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Berlin, Germany.
83
Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany.
84
Institut Curie, Department of Tumour Biology, Paris, France; Institut Curie, INSERM U830, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
85
Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon - Centre Léon Bérard, Lyon, France; INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
86
INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France.
87
Center for Medical Genetics, Ghent University, Ghent, Belgium.
88
Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
89
Prince of Wales Hospital. Sydney, Australia.
90
Ohio State University, Columbus Cancer Council, Columbus, Ohio, United States of America.
91
Division of Gynecologic Oncology, NorthShore University HealthSystem, Evanston, Illinois, United States of America.
92
Division of Gynecologic Oncology, NorthShore University HealthSystem, Chicago, Illinois, United States of America.
93
For Tufts Medical Center, Boston, Massachusetts, United States of America.
94
Yale University School of Medicine, New Haven, Connecticut, United States of America.
95
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
96
Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
97
Department of Clinical Genetics, Academic Medical Center, Amsterdam, The Netherlands.
98
Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands.
99
Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.
100
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
101
Department of Clinical Genetics, Leiden University Medical Center Leiden, Leiden, The Netherlands.
102
Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands.
103
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
104
Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
105
Department of Pathology, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands.
106
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
107
Department of Human Genetics & Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
108
The Hereditary Breast and Ovarian Cancer Research Group, Netherlands Cancer Institute, Amsterdam, The Netherlands.
109
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
110
Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain.
111
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
112
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland; Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland.
113
Department of Oncology, Landspitali University Hospital and BMC, Faculty of Medicine, University of Iceland, Reykjavik Iceland.
114
Laboratoire de Diagnostic Génétique et Service d'Onco-hématologie, Hopitaux Universitaire de Strasbourg, CHRU Nouvel Hôpital Civil, Strasbourg, France.
115
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy.
116
Department of Genetics, Portuguese Oncology Institute, Porto, and Biomedical Sciences Institute (ICBAS), Porto University, Porto, Portugal.
117
Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
118
Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia.
119
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America.
120
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
121
Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, United States of America.
122
Center for Translational Cancer Research, Department of Biological Sciences, University of Delaware, Newark, Delaware, United States of America.
123
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
124
Clinical Genetics Service, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
125
Diagnostic Molecular Genetics Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
126
Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
127
Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, Florida, United States of America.
128
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States of America.
129
Clalit National Israeli Cancer Control Center, Haifa, Israel.
130
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
131
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
132
Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
133
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, United States of America.
134
Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
135
Section of Molecular Diagnostics, Department of Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark.
136
Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
137
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
138
Sheba Medical Center, Tel Aviv, Israel.
139
Canada Research Chair in Oncogenetics, Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec and Laval University, Quebec City, Canada.
140
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
141
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain; Genotyping Unit (CeGen), Spanish National Cancer Centre (CNIO), Madrid, Spain.

Abstract

Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.

PMID:
24698998
PMCID:
PMC3974638
DOI:
10.1371/journal.pgen.1004256
[Indexed for MEDLINE]
Free PMC Article

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