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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 Antoniou 1, * Karoline Kuchenbaecker 1 Penny Soucy 2 Jonathan Beesley 3 Xiaoqing Chen 3 Lesley Mcguffog 1 Andrew Lee 1 Daniel Barrowdale 1 Sue Healey 3 Olga Sinilnikova 4, 5 Maria Caligo 6 Niklas Loman 7 Katja Harbst 7 Annika Lindblom 8 Brita Arver 9 Richard Rosenquist 10 Per Karlsson 11 Kate Nathanson 12 Susan Domchek 12 Tim Rebbeck 12 Anna Jakubowska 13 Jan Lubinski 13 Katarzyna Jaworska 13 Katarzyna Durda 13, 14 Elżbieta Złowowcka-Perłowska 13 Ana Osorio 15, 16 Mercedes Durán 17 Raquel Andrés 18 Javier Benítez 15, 16 Ute Hamann 19 Frans Hogervorst 20 Theo van Os 21 Senno Verhoef 22 Hanne Meijers-Heijboer 23 Juul Wijnen 24 Encarna Gómez Garcia 24 Marjolijn Ligtenberg 25 Mieke Kriege 26 J Margriet Collée 26 Margreet Ausems 27 Jan Oosterwijk 28 Susan Peock 1 Debra Frost 1 Steve Ellis 1 Radka Platte 1 Elena Fineberg 1 D Gareth Evans 29 Fiona Lalloo 29 Chris Jacobs 30 Ros Eeles 31 Julian Adlard 32 Rosemarie Davidson 33 Trevor Cole 34 Jackie Cook 35 Joan Paterson 36 Fiona Douglas 37 Carole Brewer 38 Shirley Hodgson 39 Patrick Morrison 40, 41 Lisa Walker 42 Mark Rogers 43 Alan Donaldson 44 Huw Dorkins 45 Andrew Godwin 46 Betsy Bove 47 Dominique Stoppa-Lyonnet 48, 49 Claude Houdayer 48 Bruno Buecher 48 Antoine de Pauw 48 Sylvie Mazoyer 5 Alain Calender 4 Mélanie Léoné 4 Brigitte Bressac- de Paillerets 50, 51 Olivier Caron 52 Hagay Sobol 53, 54 Marc Frenay 55 Fabienne Prieur 56 Sandra Ferrer 57 Isabelle Mortemousque 58 Saundra Buys 59 Mary Daly 60 Alexander Miron 61, 62 Mary Terry 63 John Hopper 64 Esther John 65 Melissa Southey 66 David Goldgar 67 Christian Singer 68 Anneliese Fink-Retter 68 Muy-Kheng Tea 68 Daphne Kaulich 68 Thomas Hansen 69 Finn Nielsen 69 Rosa Barkardottir 70 Mia Gaudet 71 Tomas Kirchhoff 72 Vijai Joseph 73 Ana Dutra-Clarke 73 Kenneth Offit 73 Marion Piedmonte 74 Judy Kirk 75 David Cohn 76 Jean Hurteau 77 John Byron 78 James Fiorica 79 Amanda Toland 80 Marco Montagna 81 Cristina Oliani 82 Evgeny Imyanitov 83 Claudine Isaacs 84 Laima Tihomirova 85 Ignacio Blanco 86 Conxi Lazaro 87 Alex Teulé 86 J Del Valle 87 Simon Gayther 88 Kunle Odunsi 89 Jenny Gross 90 Beth Karlan 90 Edith Olah 91 Soo-Hwang Teo 92 Patricia Ganz 93 Mary Beattie 94, 95 Cecelia Dorfling 96 Elizabeth van Rensburg 96 Orland Diez 97 Ava Kwong 98 Rita Schmutzler 99 Barbara Wappenschmidt 99 Christoph Engel 100 Alfons Meindl 101 Nina Ditsch 102 Norbert Arnold 103 Simone Heidemann 104 Dieter Niederacher 105 Sabine Preisler-Adams 106 Dorothea Gadzicki 107 Raymonda Varon-Mateeva 108 Helmut Deissler 109 Andrea Gehrig 110 Christian Sutter 111 Karin Kast 112 Britta Fiebig 113 Dieter Schäfer 114, 115 Trinidad Caldes 115 Miguel de la Hoya 115 Heli Nevanlinna 116 Taru Muranen 116 Bernard Lespérance 117 Amanda Spurdle 3 Susan Neuhausen 118 Yuan Ding 118 Xianshu Wang 119 Zachary Fredericksen 120 Vernon Pankratz 120 Noralane Lindor 121 Paolo Peterlongo 122 Siranoush Manoukian 123 Bernard Peissel 123 Daniela Zaffaroni 123 Bernardo Bonanni 124 Loris Bernard 125 Riccardo Dolcetti 126 Laura Papi 127 Laura Ottini 128 Paolo Radice 122 Mark Greene 129 Jennifer Loud 129 Irene Andrulis 130, 131 Hilmi Ozcelik 131, 130 Anna Mulligan 132, 133 Gord Glendon 134 Mads Thomassen 135 Anne-Marie Gerdes 136 Uffe Jensen 137 Anne-Bine Skytte 135 Torben Kruse 135 Georgia Chenevix-Trench 3 Fergus Couch 138 Jacques Simard 2 Douglas Easton 1
* Corresponding author
1 Centre for Cancer Genetic Epidemiology
2 Cancer Genomics Laboratory
3 Genetics and Population Health Division
4 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
5 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
6 Section of Genetic Oncology
7 Department of Oncology
8 Department of Clinical Genetics
9 Department of Oncology
10 Department of Genetics and Pathology
11 Department of Oncology
12 Abramson Cancer Center
13 Department of Genetics and Pathology
14 Postgraduate School of Molecular Medicine
15 Human Genetics Group
16 Biomedical Research Centre Network for Rare Diseases
17 Institute of Biology and Molecular Genetics
18 Medical Oncology Division
19 Molecular Genetics of Breast Cancer
20 Family Cancer Clinic
21 Department of Clinical Genetics
22 Department of Clinical Genetics
23 Department of Clinical Genetics
24 Department of Clinical Genetics and GROM
25 Department of Human Genetics
26 Department of Clinical Genetics
27 Department of Clinical Molecular Genetics
28 Department of Genetics
29 Genetic Medicine
30 Clinical Genetics
31 Oncogenetics Team
32 Yorkshire Regional Genetics Service
33 Ferguson-Smith Centre for Clinical Genetics
34 West Midlands Regional Genetics Service
35 Sheffield Clinical Genetics Service
36 Department of Clinical Genetics
37 Institute of Human Genetics
38 Department of Clinical Genetics
39 Medical Genetics Unit
40 Northern Ireland Regional Genetics Centre
41 Department of Medical Genetics
42 Oxford Regional Genetics Service
43 All Wales Medical Genetics Services
44 Clinical Genetics Department
45 North West Thames Regional Genetics Service
46 Department of Pathology and Laboratory Medicine
47 Clinical Molecular Genetics Laboratory
48 Service de Génétique Oncologique
49 U830 - Unité de génétique et biologie des cancers
50 Service de génétique
51 Variabilité Génétique et Maladies Humaines
52 Consultation de génétique
53 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
54 Service d'Oncologie Génétique, de Prévention et Dépistage
55 UNICANCER/CAL - Centre de Lutte contre le Cancer Antoine Lacassagne [Nice]
56 Service de Génétique Clinique Chromosomique et Moléculaire
57 Laboratoire de Génétique Chromosomique
58 Service de génétique [Tours]
59 Department of Internal Medicine
60 Division of Population Science
61 Department of Cancer Biology
62 Department of Surgery
63 Department of Epidemiology
64 Centre for Molecular , Environmental, Genetic and Analytic (MEGA) Epidemiology
65 Department of Epidemiology
66 entre for Molecular, Environmental, Genetic and Analytic (MEGA) Epidemiology
67 Department of Dermatology
68 Dept of OB/GYN and Comprehensive Cancer Center
69 Center for Genomic Medicine
70 Department of Pathology
71 Epidemiology Research Program
72 Department of Environmental Medicine
73 Clinical Genetics Service
74 Statistical and Data Center
75 Australia New Zealand (ANZGOG)
76 OSU - Ohio State University [Columbus]
77 Evanston CCOP - NorthShore University Health System; University of Chicago
78 Southern Pines Women's Health Center
79 Sarasota Memorial Healthcare
80 Department of Molecular Virology, Immunology and Medical Genetics [Colombus]
81 Immunology and Molecular Oncology Unit
82 U.O.C. di Oncologia
83 Laboratory of Molecular Oncology
84 Lombardi Comprehensive Cancer Center
85 Latvian Biomedical Research and Study Centre [Rīga]
86 Genetic Counselling Unit
87 Molecular Diagnostic Unit
88 Department of Preventive Medicine
89 Department of Gynecologic Oncology
90 Women's Cancer Program
91 Department of Molecular Genetics
92 Cancer Research Initiatives Foundation
93 Jonsson Comprehensive Cancer Center at UCLA
94 UCSF Cancer Risk Program
95 Departments of Medicine, Epidemiology, and Biostatistics
96 Cancer Genetics Laboratory
97 Oncogenetics Laboratory
98 The Hong Kong Hereditary Breast Cancer Family Registry
99 Department of Gynaecology and Obstetrics
100 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
101 Department of Gynaecology and Obstetrics
102 Department of Gynaecology and Obstetrics
103 Department of Gynaecology and Obstetrics
104 Institute of Human Genetics
105 Department of Gynaecology and Obstetrics
106 Institute of Human Genetics
107 Institute of Cell and Molecular Pathology
108 Institute of Human Genetics
109 Department of Gynaecology and Obstetrics
110 Department of Medical Genetics
111 Institute of Human Genetics
112 Department of Gynaecology and Obstetrics
113 Institute of Human Genetics
114 Institute of Human Genetics
115 Molecular Oncology Laboratory
116 Department of Obstetrics and Gynecology
117 Hemato-oncology service
118 Department of Population Sciences
119 Department of Laboratory Medicine and Pathology
120 Department of Medical Genetics
121 Department of Medical Genetics
122 Unit of Molecular Bases of Genetic Risk and Genetic Testing
123 Unit of Medical Genetics
124 Division of Cancer Prevention and Genetics
125 Department of Experimental Oncology
126 Cancer Bioimmunotherapy Unit
127 Medical Genetics Unit
128 Department of Molecular Medicine
129 Clinical Genetics Branch
130 Departments of Molecular Genetics and Laboratory Medicine and Pathobiology
131 Samuel Lunenfeld Research Institute
132 Department of Laboratory Medicine and Pathobiology
133 Department of Laboratory Medicine
134 Ontario Cancer Genetics Network
135 Department of Clinical Genetics
136 Department of Clinical Genetics [Copenhagen]
137 Department of Clinical Genetics
138 Department of Laboratory Medicine and Pathology and Health Sciences Research
Abstract : 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 12599 BRCA1 and 7132 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:0.81-0.94, P-trend=3x10^-4). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR=0.82, 95%CI:0.74-0.90, P-trend=3.1x10^-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: 0.74-0.90, P-trend=4x10^-5) and there was marginal evidence of association with ER-negative breast cancer for BRCA2 mutation carriers (HR=0.78, 95%CI:0.62-1.00, 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.
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Antonis Antoniou, Karoline Kuchenbaecker, Penny Soucy, Jonathan Beesley, Xiaoqing Chen, et al.. Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers.. Breast Cancer Research, BioMed Central, 2012, 14 (1), pp.R33. ⟨10.1186/bcr3121⟩. ⟨inserm-00681614⟩

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