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Open Access Research article

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Antonis C Antoniou1*, Karoline B Kuchenbaecker1, Penny Soucy2, Jonathan Beesley3, Xiaoqing Chen3, Lesley McGuffog1, Andrew Lee1, Daniel Barrowdale1, Sue Healey3, Olga M Sinilnikova4, Maria A Caligo5, Niklas Loman6, Katja Harbst6, Annika Lindblom7, Brita Arver8, Richard Rosenquist9, Per Karlsson10, Kate Nathanson11, Susan Domchek11, Tim Rebbeck11, Anna Jakubowska12, Jan Lubinski12, Katarzyna Jaworska12, Katarzyna Durda13, Elżbieta Złowowcka-Perłowska12, Ana Osorio14, Mercedes Durán15, Raquel Andrés16, Javier Benítez17, Ute Hamann18, Frans B Hogervorst19, Theo A van Os20, Senno Verhoef21, Hanne EJ Meijers-Heijboer22, Juul Wijnen23, Encarna B Gómez Garcia24, Marjolijn J Ligtenberg25, Mieke Kriege26, J Margriet Collée27, Margreet GEM Ausems28, Jan C Oosterwijk29, Susan Peock1, Debra Frost1, Steve D Ellis1, Radka Platte1, Elena Fineberg1, D Gareth Evans31, Fiona Lalloo31, Chris Jacobs32, Ros Eeles33, Julian Adlard34, Rosemarie Davidson35, Trevor Cole36, Jackie Cook37, Joan Paterson38, Fiona Douglas39, Carole Brewer40, Shirley Hodgson41, Patrick J Morrison42, Lisa Walker43, Mark T Rogers44, Alan Donaldson45, Huw Dorkins46, Andrew K Godwin47, Betsy Bove48, Dominique Stoppa-Lyonnet49, Claude Houdayer50, Bruno Buecher51, Antoine de Pauw52, Sylvie Mazoyer53, Alain Calender54, Mélanie Léoné54, Brigitte Bressac- de Paillerets55, Olivier Caron56, Hagay Sobol57, Marc Frenay58, Fabienne Prieur59, Sandra Fert Ferrer60, Isabelle Mortemousque61, Saundra Buys63, Mary Daly64, Alexander Miron65, Mary Beth Terry66, John L Hopper67, Esther M John68, Melissa Southey69, David Goldgar70, Christian F Singer71, Anneliese Fink-Retter71, Muy-Kheng Tea71, Daphne Geschwantler Kaulich71, Thomas VO Hansen72, Finn C Nielsen72, Rosa B Barkardottir73, Mia Gaudet74, Tomas Kirchhoff75, Vijai Joseph76, Ana Dutra-Clarke76, Kenneth Offit76, Marion Piedmonte77, Judy Kirk78, David Cohn79, Jean Hurteau80, John Byron81, James Fiorica82, Amanda E Toland83, Marco Montagna84, Cristina Oliani85, Evgeny Imyanitov86, Claudine Isaacs87, Laima Tihomirova88, Ignacio Blanco89, Conxi Lazaro90, Alex Teulé89, J Del Valle90, Simon A Gayther91, Kunle Odunsi92, Jenny Gross93, Beth Y Karlan93, Edith Olah94, Soo-Hwang Teo95, Patricia A Ganz96, Mary S Beattie97, Cecelia M Dorfling98, Elizabeth Jansen van Rensburg98, Orland Diez99, Ava Kwong100, Rita K Schmutzler101, Barbara Wappenschmidt101, Christoph Engel102, Alfons Meindl103, Nina Ditsch104, Norbert Arnold105, Simone Heidemann106, Dieter Niederacher107, Sabine Preisler-Adams108, Dorothea Gadzicki109, Raymonda Varon-Mateeva110, Helmut Deissler111, Andrea Gehrig112, Christian Sutter113, Karin Kast114, Britta Fiebig115, Dieter Schäfer116, Trinidad Caldes117, Miguel de la Hoya117, Heli Nevanlinna118, Taru A Muranen118, Bernard Lespérance119, Amanda B Spurdle3, Susan L Neuhausen121, Yuan C Ding121, Xianshu Wang122, Zachary Fredericksen123, Vernon S Pankratz123, Noralane M Lindor124, Paolo Peterlongo125, Siranoush Manoukian126, Bernard Peissel126, Daniela Zaffaroni126, Bernardo Bonanni127, Loris Bernard128, Riccardo Dolcetti129, Laura Papi130, Laura Ottini131, Paolo Radice125, Mark H Greene132, Jennifer T Loud132, Irene L Andrulis133, Hilmi Ozcelik134, Anna Marie Mulligan135, Gord Glendon136, Mads Thomassen137, Anne-Marie Gerdes138, Uffe B Jensen139, Anne-Bine Skytte140, Torben A Kruse137, Georgia Chenevix-Trench3, Fergus J Couch141, Jacques Simard142, Douglas F Easton1, CIMBA, SWE-BRCA6, HEBON30, EMBRACE1, GEMO Collaborators Study 62 and kConFab Investigators120

Author Affiliations

1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Worts Causeway, Cambridge CB1 8RN, UK

2 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City, QC Canada

3 Genetics and Population Health Division, Queensland Institute of Medical Research, 300 Herston Rd, Herston, Brisbane, QLD 4006, Australia

4 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, 28 rue Laënnec, Lyon 69373, France and INSERM U1052, CNRS UMR5286, Université Lyon 1, Cancer Research Center of Lyon, 28 rue Laënnec, Lyon 69373, France

5 Section of Genetic Oncology, Dept. of Laboratory Medicine, University and University Hospital of Pisa, Via Roma 57, 56125 Pisa, Italy

6 Department of Oncology, Lund University Hospital, Lund, Sweden

7 Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden

8 Department of Oncology, Karolinska University Hospital, Stockholm, Sweden

9 Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

10 Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

11 Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

12 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland

13 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin and Postgraduate School of Molecular Medicine, Warsaw Medical University, Warsaw, Poland

14 Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain and Spanish Network on Rare Diseases (CIBERER)

15 Institute of Biology and Molecular Genetics. Universidad de Valladolid (IBGM-UVA), Valladolid, Spain

16 Oncology unit. Hospital clinico Universitario "Lozano Blesa", Zaragoza, Spain

17 Human Genetics Group and Genotyping Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain and Spanish Network on Rare Diseases (CIBERER)

18 Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

19 Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands

20 Department of Clinical Genetics, Academic Meical Center, Amsterdam, The Netherlands

21 Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands

22 Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands

23 Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands

24 Department of Clinical Genetics and GROM, School for Oncology and Developmental Biology, MUMC, Maastricht, The Netherlands

25 Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands

26 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands

27 Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, The Netherlands

28 Department of Medical Genetics, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, The Netherlands

29 Department of Genetics, University Medical Center, Groningen University, Groningen, The Netherlands

30 Netherlands Cancer Institute, Amsterdam, The Netherlands

31 Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

32 Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK

33 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, UK

34 Yorkshire Regional Genetics Service, Leeds, UK

35 Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Glasgow, UK

36 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK

37 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK

38 Department of Clinical Genetics, East Anglian Regional Genetics Service, Addenbrookes Hospital, Cambridge, UK

39 Institute of Genetic Medicine, Centre for Life, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK

40 Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK

41 Medical Genetics Unit, St George's, University of London, UK

42 Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, and Department of Medical Genetics, Queens University Belfast, Belfast UK

43 Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK

44 All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK

45 Clinical Genetics Department, St Michael's Hospital, Bristol, UK

46 North West Thames Regional Genetics Service, Kennedy-Galton Centre, Harrow, UK

47 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA

48 Clinical Molecular Genetics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA

49 Service de Génétique Oncologique, Institut Curie, Paris, France, Unité INSERM U830, Institut Curie, Paris, France, Université Paris Descartes, Faculté de Médecine, Paris, France

50 Service de Génétique Oncologique, Institut Curie, Paris, France and Université Paris Descartes, Faculté de Pharmacie, Paris, France

51 Service de Génétique Oncologique, Institut Curie, 26 rue d'Ulm, Paris, France

52 Service de Génétique Oncologique, Institut Curie, Paris, France

53 INSERM U1052, CNRS UMR5286, Université Lyon 1, Centre de Recherche en Cancérologie de Lyon, Lyon, France

54 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France

55 Service de Génétique, Institut de Cancérologie Gustave Roussy, Villejuif, France and INSERM U946, Fondation Jean Dausset, Paris, France

56 Consultation de Génétique, Département de Médecine, Institut de Cancérologie Gustave Roussy, Villejuif, France

57 Département Oncologie génétique, Prévention et Dépistage, INSERM CIC-P9502, Institut Paoli-Calmettes/Université d'Aix-Marseille II, Marseille, France

58 Centre Antoine Lacassagne, Nice, France

59 Service de Génétique Clinique Chromosomique et Moléculaire, Centre Hospitalier Universitaire de St Etienne, St Etienne, France

60 Laboratoire de Génétique Chromosomique, Hôtel Dieu Centre Hospitalier, BP 1125 Chambéry, France

61 Service de Génétique, Centre Hospitalier Universitaire Bretonneau, Tours, France

62 Cancer Genetics Network "Groupe Génétique et Cancer", Fédération Nationale des Centres de Lutte Contre le Cancer, France

63 Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT 84112, USA

64 Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA

65 Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Surgery, Harvard Medical School, 27 Drydock Avenue, Boston, MA 02210, USA

66 Department of Epidemiology, Columbia University, New York, NY, USA

67 Centre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology, Melbourne School of Population Health, Level 1, 723 Swanston Street, The University of Melbourne, VIC 3010, Australia

68 Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA 94538, USA

69 Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Australia

70 Department of Dermatology, University of Utah School of Medicine, 30 North 1900 East, SOM 4B454, Salt Lake City, UT 84132, USA

71 Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

72 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

73 Department of Pathology, Landspitali - University Hospital, Reykjavik Iceland and Faculty of Medicine, University of Iceland, Reykjavik, Iceland

74 Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA

75 Department of Environmental Medicine, NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

76 Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY, USA

77 Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY, USA

78 Australia New Zealand (ANZGOG), Westmead Hospital, Sydney, Australia

79 Ohio State University, Columbus Cancer Council, Columbus, OH, USA

80 Evanston CCOP - NorthShore University Health System; University of Chicago, Chicago, IL, USA

81 Southern Pines Women's Health Center, P.C., University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

82 Sarasota Memorial Healthcare, Tufts Medical Center, Sarasota, Florida, USA

83 Department of Molecular Virology, Immunology and Medical Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA

84 Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padua, Italy

85 U.O.C. di Oncologia, ULSS5 Ovest Vicentino, Italy

86 Laboratory of Molecular Oncology, N.N. Petrov Institute of Oncology, St.-Petersburg, Russia

87 Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA

88 Latvian Biomedical Research and Study Centre, Latvia

89 Genetic Counselling Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain

90 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL-Catalan Institute of Oncology, Barcelona, Spain

91 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

92 Department of Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA

93 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center, Los Angeles, CA, USA

94 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary

95 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Malaysia and University Malaya Cancer Research Institute, University Malaya Medical Centre, Kuala Lumpur, Malaysia

96 Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA

97 UCSF Cancer Risk Program, University of California, San Francisco, CA; UCSF Departments of Medicine, Epidemiology, and Biostatistics, Sand Francisco, CA, USA

98 Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, South Africa

99 Oncogenetics Laboratory. Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital. Barcelona, Spain

100 The Hong Kong Hereditary Breast Cancer Family Registry; The Universtiy of Hong Kong; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong

101 Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO), University hospital of Cologne, Cologne, Germany

102 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

103 Department of Gynaecology and Obstetrics, Division of Tumour Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany

104 Department of Gynaecology and Obstetrics, Ludwig-Maximilian University Munich, Munich, Germany

105 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany

106 Institute of Human Genetics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany

107 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University, Düsseldorf, Germany

108 Institute of Human Genetics, University of Münster, Münster, Germany

109 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany

110 Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany

111 Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany

112 Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Würzburg, Germany

113 Institute of Human Genetics, Department of Human Genetics, University Hospital Heidelberg, Germany

114 Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University. Dresden, Germany

115 Institute of Human Genetics, University Regensburg, Regensbirg. Germany

116 Institute of Human Genetics, University Hospital Frankfurt a.M., Germany Molecular Oncology Laboratory, Hospital Clinico San Carlos, Madrid, Spain

117 Molecular Oncology Laboratory, Hospital Clinico San Carlos, Martin Lagos s/n, Madrid, Spain

118 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Biomedicum Helsinki, P.O. BOX 700, 00029 HUS, Helsinki, Finland

119 Faculty of Medicine - Medicine and Medical Specialties, Université de Montréal Hemato-oncology service, Hôpital du Sacré-Coeur de Montréal, 5400 Gouin Blvd West Montreal, QC, Canada

120 Peter MacCallum Cancer Center, Melbourne, VIC, Australia

121 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA

122 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

123 Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA

124 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA

125 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Milan, Italy and IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy

126 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale Tumouri (INT), Milan, Italy

127 Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), Milan Italy

128 Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy and Consortium for Genomics Technology (Cogentech), Milan, Italy

129 Cancer Bioimmunotherapy Unit, Centro di Riferimento Oncologico, IRCCS, Aviano (PN), Italy

130 Medical Genetics Unit, Department of Clinical Physiopathology, University of Florence, Firenze, Italy

131 Department of Molecular Medicine, "Sapienza" University of Rome, Rome, Italy

132 Clinical Genetics Branch, DCEG, NCI; Room EPS 7032, Rockville, MD 20852, USA

133 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; Cancer Care Ontario, Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada

134 Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON; Department of Laboratory Medicine and Pathobiology, University of Toronto, ON, Canada

135 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine, and the Keenan Research Centre of the Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada

136 Ontario Cancer Genetics Network: Cancer Care Ontario, Toronto, ON, Canada

137 Department of Clinical Genetics, Odense University Hospital, Denmark

138 Department of Clincial Genetics, Rigshospital and Copenhagen University, Denmark

139 Department of Clinical Genetics, Skejby Hospital, Aarhus, Denmark

140 Department of Clinical Genetics, Vejle Hospital, Denmark

141 Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA

142 Cancer Genomics Laboratory, Centre Hospitalier Universitaire de Québec, 2705 Laurier Boulevard, T3-57, Quebec City and Canada Research Chair in Oncogenetics, Department of Molecular Medicine, Faculty of Medicine, Laval University, QC, Canada

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Breast Cancer Research 2012, 14:R33  doi:10.1186/bcr3121

Published: 20 February 2012

Abstract

Introduction

Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2).

Methods

To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework.

Results

Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 × 10-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 × 10-5, P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df-P = 0.007; rs1292011 2df-P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 × 10-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049).

Conclusions

The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.