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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.

Anna Marie 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 Van 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 Birk 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 Chun 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 Beth 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 CHU 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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https://www.hal.inserm.fr/inserm-00670601
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Submitted on : Wednesday, February 15, 2012 - 5:05:45 PM
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INSERM | UNIV-PARIS5 | UNIV-PARIS13 | HCL | CNRS | UNIV-LYON1 | FNCLCC | BERGONIE | CURIE | BACLESSE | STRAUSS | COMUE-NORMANDIE | PSL | CRCL | UDL | SORBONNE-PARIS-NORD | UNIV-PARIS

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Anna Marie Mulligan, Fergus Couch, Daniel Barrowdale, Susan Domchek, Diana Eccles, et al.. 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.. Breast Cancer Research, BioMed Central, 2011, 13 (6), pp.R110. ⟨10.1186/bcr3052⟩. ⟨inserm-00670601⟩

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