Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Anna Mulligan; Fergus Couch; Daniel Barrowdale; Susan Domchek; Diana Eccles; Heli Nevanlinna; Susan Ramus; Mark Robson; Mark Sherman; Amanda Spurdle; Barbara Wappenschmidt; Andrew Lee; Lesley Mcguffog; Sue Healey; Olga Sinilnikova; Ramunas Janavicius; Thomas Hansen; Finn Nielsen; Bent Ejlertsen; Ana Osorio; Iván Muñoz-Repeto; Mercedes Durán; Javier Godino; Maroulio Pertesi; Javier Benítez; Paolo Peterlongo; Siranoush Manoukian; Bernard Peissel; Daniela Zaffaroni; Elisa Cattaneo; Bernardo Bonanni; Alessandra Viel; Barbara Pasini; Laura Papi; Laura Ottini; Antonella Savarese; Loris Bernard; Paolo Radice; Ute Hamann; Martijn Verheus; Hanne Meijers-Heijboer; Juul Wijnen; Encarna Gómez García; Marcel Nelen; C Marleen Kets; Caroline Seynaeve; Madeleine Tilanus-Linthorst; Rob van der Luijt; Theo Os; Matti Rookus; Debra Frost; J Louise Jones; D Gareth Evans; Fiona Lalloo; Ros Eeles; Louise Izatt; Julian Adlard; Rosemarie Davidson; Jackie Cook; Alan Donaldson; Huw Dorkins; Helen Gregory; Jacqueline Eason; Catherine Houghton; Julian Barwell; Lucy Side; Emma Mccann; Alex Murray; Susan Peock; Andrew Godwin; Rita Schmutzler; Kerstin Rhiem; Christoph Engel; Alfons Meindl; Ina Ruehl; Norbert Arnold; Dieter Niederacher; Christian Sutter; Helmut Deissler; Dorothea Gadzicki; Karin Kast; Sabine Preisler-Adams; Raymonda Varon-Mateeva; Ines Schoenbuchner; Britta Fiebig; Wolfram Heinritz; Dieter Schäfer; Heidrun Gevensleben; Virginie Caux-Moncoutier; Marion Fassy-Colcombet; François Cornelis; Sylvie Mazoyer; Mélanie Léoné; Nadia Boutry-Kryza; Agnès Hardouin; Pascaline Berthet; Danièle Muller; Jean-Pierre Fricker; Isabelle Mortemousque; Pascal Pujol; Isabelle Coupier; Marine Lebrun; Caroline Kientz; Michel Longy; Nicolas Sevenet; Dominique Stoppa-Lyonnet; Claudine Isaacs; Trinidad Caldes; Miguel de la Hoya; Tuomas Heikkinen; Kristiina Aittomäki; Ignacio Blanco; Conxi Lazaro; Rosa Barkardottir; Penny Soucy; Martine Dumont; Jacques Simard; Marco Montagna; Silvia Tognazzo; Emma d'Andrea; Stephen Fox; Max Yan; Tim Rebbeck; Olufunmilayo Olopade; Jeffrey Weitzel; Henry Lynch; Patricia Ganz; Gail Tomlinson; Xianshu Wang; Zachary Fredericksen; Vernon Pankratz; Noralane Lindor; Csilla Szabo; Kenneth Offit; Rita Sakr; Mia Gaudet; Jasmine Bhatia; Noah Kauff; Christian Singer; Muy-Kheng Tea; Daphne Gschwantler-Kaulich; Anneliese Fink-Retter; Phuong Mai; Mark Greene; Evgeny Imyanitov; Frances O'Malley; Hilmi Ozcelik; Gordon Glendon; Amanda Toland; Anne-Marie Gerdes; Mads Thomassen; Torben Kruse; Uffe Jensen; Anne-Bine Skytte; Maria Caligo; Maria Soller; Karin Henriksson; von Anna Wachenfeldt; Brita Arver; Marie Stenmark-Askmalm; Per Karlsson; Yuan Ding; Susan Neuhausen; Mary Beattie; Paul Pharoah; Kirsten Moysich; Katherine Nathanson; Beth Karlan; Jenny Gross; Esther John; Mary Daly; Saundra Buys; Melissa Southey; John Hopper; Mary Terry; Wendy Chung; Alexander Miron; David Goldgar; Georgia Chenevix-Trench; Douglas Easton; Irene Andrulis; Antonis Antoniou

doi:10.1186/bcr3052

Journal articles

Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

Anna Mulligan ^{1, 2} Fergus Couch ³ Daniel Barrowdale ⁴ Susan Domchek ⁵ Diana Eccles ⁶ Heli Nevanlinna ⁷ Susan Ramus ⁸ Mark Robson ⁹ Mark Sherman ¹⁰ Amanda Spurdle ¹¹ Barbara Wappenschmidt ¹² Andrew Lee ⁴ Lesley Mcguffog ⁴ Sue Healey ¹¹ Olga Sinilnikova ^{13, 14} Ramunas Janavicius ^{15, 16} Thomas Hansen ¹⁷ Finn Nielsen ¹⁷ Bent Ejlertsen ¹⁸ Ana Osorio ¹⁹ Iván Muñoz-Repeto ¹⁹ Mercedes Durán ²⁰ Javier Godino ²¹ Maroulio Pertesi ²² Javier Benítez ¹⁹ Paolo Peterlongo ^{23, 24} Siranoush Manoukian ²⁵ Bernard Peissel ²⁵ Daniela Zaffaroni ²⁵ Elisa Cattaneo ²⁵ Bernardo Bonanni ²⁶ Alessandra Viel ²⁷ Barbara Pasini ²⁸ Laura Papi ²⁹ Laura Ottini ³⁰ Antonella Savarese ³¹ Loris Bernard ³² Paolo Radice ²³ Ute Hamann ³³ Martijn Verheus ³⁴ Hanne Meijers-Heijboer ³⁵ Juul Wijnen ³⁶ Encarna Gómez García ³⁷ Marcel Nelen ³⁸ C Marleen Kets ³⁸ Caroline Seynaeve ³⁹ Madeleine Tilanus-Linthorst ⁴⁰ Rob van der Luijt ⁴¹ Theo Os ⁴² Matti Rookus ³⁴ Debra Frost ⁴ J Louise Jones ⁴³ D Gareth Evans ⁴⁴ Fiona Lalloo ⁴⁴ Ros Eeles ⁴⁵ Louise Izatt ⁴⁶ Julian Adlard ⁴⁷ Rosemarie Davidson ⁴⁸ Jackie Cook ⁴⁹ Alan Donaldson ⁵⁰ Huw Dorkins ⁵¹ Helen Gregory ⁵² Jacqueline Eason ⁵³ Catherine Houghton ⁵⁴ Julian Barwell ⁵⁵ Lucy Side ⁵⁶ Emma Mccann ⁵⁷ Alex Murray ⁵⁷ Susan Peock ⁴ Andrew Godwin ⁵⁸ Rita Schmutzler ¹² Kerstin Rhiem ¹² Christoph Engel ⁵⁹ Alfons Meindl ⁶⁰ Ina Ruehl ⁶¹ Norbert Arnold ⁶² Dieter Niederacher ⁶³ Christian Sutter ⁶⁴ Helmut Deissler ⁶⁵ Dorothea Gadzicki ⁶⁶ Karin Kast ⁶⁷ Sabine Preisler-Adams ⁶⁸ Raymonda Varon-Mateeva ⁶⁹ Ines Schoenbuchner ⁷⁰ Britta Fiebig ⁷¹ Wolfram Heinritz ⁷¹ Dieter Schäfer ⁷² Heidrun Gevensleben ⁷³ Virginie Caux-Moncoutier ⁷⁴ Marion Fassy-Colcombet ⁷⁴ François Cornelis ^{75, 76, 77} Sylvie Mazoyer ¹⁴ Mélanie Léoné ¹³ Nadia Boutry-Kryza ¹³ Agnès Hardouin ⁷⁸ Pascaline Berthet ⁷⁸ Danièle Muller ⁷⁹ Jean-Pierre Fricker ⁷⁹ Isabelle Mortemousque ⁸⁰ Pascal Pujol ⁸¹ Isabelle Coupier ⁸¹ Marine Lebrun ⁸² Caroline Kientz ⁸² Michel Longy ⁸³ Nicolas Sevenet ⁸³ Dominique Stoppa-Lyonnet ^{74, 84} Claudine Isaacs ⁸⁵ Trinidad Caldes ⁸⁶ Miguel de la Hoya ⁸⁶ Tuomas Heikkinen ⁷ Kristiina Aittomäki ⁸⁷ Ignacio Blanco ⁸⁸ Conxi Lazaro ⁸⁸ Rosa Barkardottir ^{89, 90} Penny Soucy ⁹¹ Martine Dumont ⁹¹ Jacques Simard ^{91, 92} Marco Montagna ⁹³ Silvia Tognazzo ⁹³ Emma d'Andrea ⁹⁴ Stephen Fox ⁹⁵ Max Yan ⁹⁶ Tim Rebbeck ⁹⁷ Olufunmilayo Olopade ⁹⁸ Jeffrey Weitzel ⁹⁹ Henry Lynch ¹⁰⁰ Patricia Ganz ¹⁰¹ Gail Tomlinson ^{102, 103} Xianshu Wang ³ Zachary Fredericksen ¹⁰⁴ Vernon Pankratz ¹⁰⁴ Noralane Lindor ¹⁰⁵ Csilla Szabo ¹⁰⁶ Kenneth Offit ⁹ Rita Sakr ⁹ Mia Gaudet ¹⁰⁷ Jasmine Bhatia ⁹ Noah Kauff ⁹ Christian Singer ¹⁰⁸ Muy-Kheng Tea ¹⁰⁴ Daphne Gschwantler-Kaulich ¹⁰⁴ Anneliese Fink-Retter ¹⁰⁴ Phuong Mai ¹⁰ Mark Greene ¹⁰⁴ Evgeny Imyanitov ¹⁰⁹ Frances O'Malley ^{2, 1} Hilmi Ozcelik ^{2, 110} Gordon Glendon ¹¹¹ Amanda Toland ¹¹² Anne-Marie Gerdes ¹¹³ Mads Thomassen ¹¹⁴ Torben Kruse ¹⁰⁴ Uffe Jensen ¹¹⁵ Anne-Bine Skytte ¹¹⁶ Maria Caligo ¹¹⁷ Maria Soller ¹¹⁸ Karin Henriksson ¹¹⁹ von Anna Wachenfeldt ¹²⁰ Brita Arver ¹⁰⁴ Marie Stenmark-Askmalm ¹²¹ Per Karlsson ¹²² Yuan Ding ¹²³ Susan Neuhausen ¹⁰⁴ Mary Beattie ¹²⁴ Paul Pharoah ¹²⁵ Kirsten Moysich ¹²⁶ Katherine Nathanson ⁵ Beth Karlan ¹²⁷ Jenny Gross ¹⁰⁴ Esther John ¹²⁸ Mary Daly ¹²⁹ Saundra Buys ¹³⁰ Melissa Southey ¹³¹ John Hopper ¹³² Mary Terry ¹³³ Wendy Chung ¹⁰⁴ Alexander Miron ¹³⁴ David Goldgar ¹³⁵ Georgia Chenevix-Trench ¹¹ Douglas Easton ⁴ Irene Andrulis ^{2, 110} Antonis Antoniou ^{4, *}

* Corresponding author

1 Department of Laboratory Medicine

2 Department of Laboratory Medicine and Pathobiology

3 Department of Laboratory Medicine and Pathology

4 Centre for Cancer Genetic Epidemiology

5 Department of Medicine

6 Faculty of Medicine

7 Department of Obstetrics and Gynecology

8 Department of Preventive Medicine

9 Department of Medicine

10 Division of Cancer Epidemiology and Genetics

11 Queensland Institute of Medical Research

12 Department of Gynaecology and Obstetrics

13 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents

14 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon

15 Department of Molecular and Regenerative Medicine, Hematology, Oncology and Transfusion Medicine Center

16 State Research Institute Innovative Medicine Center

17 Center for Genomic Medicine

18 Department of Oncology

19 Human Genetics Group

20 Institute of Biology and Molecular Genetics

21 IIS - Instituto de investigación sanitaria de Aragón

22 Molecular Diagnostics Laboratory

23 Unit of Molecular Bases of Genetic Risk and Genetic Testing

24 Fondazione Istituto FIRC di Oncologia Molecolare

25 Unit of Medical Genetics

26 Division of Cancer Prevention and Genetics

27 Unit of Experimental Oncology 1

28 Department of Genetics, Biology and Biochemistry

29 Medical Genetics Unit

30 Department of Molecular Medicine

31 Division of Medical Oncology

32 Department of Experimental Oncology

33 Molecular Genetics of Breast Cancer

34 Department of Epidemiology

35 Department of Clinical Genetics

36 Department of Human Genetics and Department of Clinical Genetics

37 Department of Clinical Genetics and GROW

38 Department of Human Genetics

39 Department of Medical Oncology

40 Department of Surgical Oncology

41 Department of Clinical Molecular Genetics

42 Department of Clinical Genetics

43 Barts Cancer Institute

44 Genetic Medicine

45 Oncogenetics Team

46 Clinical Genetics

47 Yorkshire Regional Genetics Service

48 Ferguson-Smith Centre for Clinical Genetics

49 Sheffield Clinical Genetics Service

50 Clinical Genetics Department

51 North West Thames Regional Genetics Service

52 North of Scotland Regional Genetics Service

53 Nottingham Clinical Genetics Service

54 Cheshire and Merseyside Clinical Genetics Service

55 Leicestershire Clinical Genetics Service

56 North East Thames Regional Genetics Service

57 All Wales Medical Genetics Services

58 Department of Pathology and Laboratory Medicine

59 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]

60 Department of Gynaecology and Obstetrics

61 Department of Gynaecology and Obstetrics

62 Department of Gynaecology and Obstetrics

63 Department of Gynaecology and Obstetrics

64 Institute of Human Genetics

65 Department of Gynaecology and Obstetrics

66 Institute of Cell and Molecular Pathology

67 Department of Gynaecology and Obstetrics

68 Institute of Human Genetics

69 Institute of Human Genetics

70 Department of Medical Genetic

71 Institute of Human Genetics

72 Institute of Human Genetics

73 Breakthrough Breast Cancer Research Centre

74 Service de Génétique Oncologique

75 Service de génétique [Avicenne]

76 Centre Hospitalier Sud Francilien

77 Centre Hospitalier Universitaire Clermont-Ferrand

78 UNICANCER/CRLC - Centre Régional de Lutte contre le Cancer François Baclesse [Caen]

79 Unité d'oncogénétique

80 Service de génétique [Tours]

81 Service de génétique médicale [Montpellier]

82 Service de Génétique Clinique Chromosomique et Moléculaire

83 VINCO - Validation et identification de nouvelles cibles en oncologie

84 U830 - Unité de génétique et biologie des cancers

85 Lombardi Comprehensive Cancer Center

86 Molecular Oncology Laboratory

87 Department of Clinical Genetics

88 Hereditary Cancer Program

89 Department of Pathology

90 Faculty of Medicine

91 Cancer Genomics Laboratory

92 Research Chair in Oncogenetics

93 Immunology and Molecular Oncology Unit

94 Department of Oncology and Surgical Sciences

95 Peter MacCallum Cancer Centre

96 Department of Anatomical Pathology

97 Abramson Cancer Center

98 University of Chicago

99 City of Hope Comprehensive Cancer Center and Department of Population Sciences

100 Departments of Medicine, and Preventive Medicine and Public Health

101 Jonsson Comprehensive Cancer Center

102 Department of Internal Medicine

103 Department of Pediatrics

104 Department of Medical Genetics

105 Department of Medical Genetics

106 University of Delaware [Newark]

107 Epidemiology Research Program

108 Department of Obstetrics/Gynaecology and Comprehensive Cancer Center

109 Laboratory of Molecular Oncology

110 Samuel Lunenfeld Research Institute

111 Prevention & Cancer Control

112 Departments of Molecular VirologyImmunology and Medical Genetics and Internal Medicine

113 Clinical Genetics

114 Clinical Genetics

115 Department of Clinical Genetics

116 Clinical Genetics

117 Section of Genetic Oncology

118 Department of Clinical Genetics

119 Oncological Centre

120 Department of Oncology

121 Department of Clinical and Experimental Medicine

122 Department of Oncology

123 Department of Population Sciences

124 UCSF Cancer Risk Program and Departments of Medicine and Epidemiology and Biostatistics

125 Department of Oncology

126 Department of Cancer Prevention and Control

127 Women's Cancer Program

128 Department of Epidemiology

129 Fox Chase Cancer Center

130 Department of Oncological Sciences

131 Genetic Epidemiology Laboratory

132 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology

133 Department of Epidemiology

134 Department of Cancer Biology

135 Department of Dermatology

Abstract : ABSTRACT: INTRODUCTION: Previous studies have demonstrated that common breast cancer susceptibility alleles are differentially associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers. It is currently unknown how these alleles are associated with different breast cancer subtypes in BRCA1 and BRCA2 mutation carriers defined by estrogen (ER) or progesterone receptor (PR) status of the tumour. METHODS: We used genotype data on up to 11,421 BRCA1 and 7,080 BRCA2 carriers, of whom 4,310 had been affected with breast cancer and had information on either ER or PR status of the tumour, to assess the associations of 12 loci with breast cancer tumour characteristics. Associations were evaluated using a retrospective cohort approach. RESULTS: The results suggested stronger associations with ER-positive breast cancer than ER-negative for 11 loci in both BRCA1 and BRCA2 carriers. Among BRCA1 carriers, single nucleotide polymorphism (SNP) rs2981582 (FGFR2) exhibited the biggest difference based on ER status (per-allele hazard ratio (HR) for ER-positive = 1.35, 95% CI: 1.17 to 1.56 vs HR = 0.91, 95% CI: 0.85 to 0.98 for ER-negative, P-heterogeneity = 6.5 × 10-6). In contrast, SNP rs2046210 at 6q25.1 near ESR1 was primarily associated with ER-negative breast cancer risk for both BRCA1 and BRCA2 carriers. In BRCA2 carriers, SNPs in FGFR2, TOX3, LSP1, SLC4A7/NEK10, 5p12, 2q35, and 1p11.2 were significantly associated with ER-positive but not ER-negative disease. Similar results were observed when differentiating breast cancer cases by PR status. CONCLUSIONS: The associations of the 12 SNPs with risk for BRCA1 and BRCA2 carriers differ by ER-positive or ER-negative breast cancer status. The apparent differences in SNP associations between BRCA1 and BRCA2 carriers, and non-carriers, may be explicable by differences in the prevalence of tumour subtypes. As more risk modifying variants are identified, incorporating these associations into breast cancer subtype-specific risk models may improve clinical management for mutation carriers.

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Journal articles

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Life Sciences [q-bio] / Cancer

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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

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Common breast cancer susceptibility alleles are associated with tumour subtypes in BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2.

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