Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers.
Logan Walker
(1)
,
Zachary Fredericksen
(2)
,
Xianshu Wang
(2)
,
Robert Tarrell
(2)
,
Vernon Pankratz
(2)
,
Noralane Lindor
(2)
,
Jonathan Beesley
(1)
,
Sue Healey
(1)
,
Xiaoqing Chen
(1)
,
Dominique Stoppa-Lyonnet
(3)
,
Carole Tirapo
(3)
,
Sophie Giraud
(4)
,
Sylvie Mazoyer
(5)
,
Danièle Muller
(6)
,
Jean-Pierre Fricker
(6)
,
Capucine Delnatte
(7)
,
Rita Schmutzler
(8)
,
Barbara Wappenschmidt
(8)
,
Christoph Engel
(9)
,
Ines Schönbuchner
(10)
,
Helmut Deissler
(11)
,
Alfons Meindl
(12)
,
Frans Hogervorst
(13)
,
Martijn Verheus
(14)
,
Maartje Hooning
(15)
,
Ans van den Ouweland
(16)
,
Marcel Nelen
(17)
,
Margreet Ausems
(18)
,
Cora Aalfs
(19)
,
Christi van Asperen
(20)
,
Peter Devilee
(21)
,
Monique Gerrits
(22)
,
Quinten Waisfisz
(23)
,
Csilla Szabo
(2)
,
Douglas Easton
(24)
,
Susan Peock
(24)
,
Margaret Cook
(24)
,
Clare Oliver
(24)
,
Debra Frost
(24)
,
Patricia Harrington
(25)
,
Gareth D. Evans
(26)
,
Fiona Lalloo
(26)
,
Ros Eeles
(27)
,
Louise Izatt
(28)
,
Carol Chu
(29)
,
Rosemarie Davidson
(30)
,
Diana Eccles
(31)
,
Kai-Ren Ong
(32)
,
Jackie Cook
(33)
,
Tim Rebbeck
(34)
,
Katherine Nathanson
(34)
,
Susan Domchek
(34)
,
Christian Singer
(35)
,
Daphne Gschwantler-Kaulich
(35)
,
Anne-Catharina Dressler
(35)
,
Georg Pfeiler
(35)
,
Andrew Godwin
(36)
,
Tuomas Heikkinen
(37)
,
Heli Nevanlinna
(37)
,
Bjarni Agnarsson
(38)
,
Maria Adelaide Caligo
(39)
,
Håkan Olsson
(40)
,
Ulf Kristoffersson
(41)
,
Annelie Liljegren
(42)
,
Brita Arver
(42)
,
Per Karlsson
(43)
,
Beatrice Melin
(44)
,
Olga Sinilnikova
(5, 6)
,
Lesley Mcguffog
(24)
,
Antonis Antoniou
(24)
,
Georgia Chenevix-Trench
(1)
,
Amanda Spurdle
(1)
,
Fergus Couch
(2)
1
Division of Genetics and Population Health
2 Department of Laboratory Medicine and Pathology
3 Pathologie moléculaire des cancers
4 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
5 GMSC - Génétique moléculaire, signalisation et cancer
6 Unité d'Oncogénétique
7 Centre René Gauducheau
8 Centre for Hereditary Breast and Ovarian Cancer
9 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
10 Institute of Human Genetics
11 Department of Obstetrics and Gynaecology
12 Department of Obstetrics and Gynaecology
13 Family Cancer Clinic
14 Department of Epidemiology
15 Department of Medical Oncology
16 Department of Clinical Genetics
17 Department of Human Genetics
18 Department of Medical Genetics
19 Department of Clinical Genetics
20 Department of Clinical Genetics
21 Department of Human Genetics & Department of Pathology
22 Department of Genetics and Cell Biology
23 Department of Clinical Genetics
24 Strangeways Research Laboratory
25 Centre for Cancer Genetic Epidemiology [Cambridge]
26 Genetic Medicine
27 Oncogenetics Team
28 Clinical Genetics Department
29 Yorkshire Regional Genetics Service
30 Ferguson-Smith Centre for Clinical Genetics
31 Wessex Clinical Genetics Service
32 West Midlands Regional Genetics Service
33 Sheffield Clinical Genetics Service
34 Abramson Cancer Center
35 Division of Special Gynecology
36 Women's Cancer Program
37 Department of Obstetrics and Gynecology
38 Department of Pathology
39 Section of Genetic Oncology
40 Department of Oncology
41 Department of Clinical Genetics
42 Department of Oncology
43 Department of Oncology
44 Department of Radiation Sciences and Oncology
2 Department of Laboratory Medicine and Pathology
3 Pathologie moléculaire des cancers
4 Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents
5 GMSC - Génétique moléculaire, signalisation et cancer
6 Unité d'Oncogénétique
7 Centre René Gauducheau
8 Centre for Hereditary Breast and Ovarian Cancer
9 IMISE - Institute for Medical Informatics, Statistics and Epidemiology [Leipzig]
10 Institute of Human Genetics
11 Department of Obstetrics and Gynaecology
12 Department of Obstetrics and Gynaecology
13 Family Cancer Clinic
14 Department of Epidemiology
15 Department of Medical Oncology
16 Department of Clinical Genetics
17 Department of Human Genetics
18 Department of Medical Genetics
19 Department of Clinical Genetics
20 Department of Clinical Genetics
21 Department of Human Genetics & Department of Pathology
22 Department of Genetics and Cell Biology
23 Department of Clinical Genetics
24 Strangeways Research Laboratory
25 Centre for Cancer Genetic Epidemiology [Cambridge]
26 Genetic Medicine
27 Oncogenetics Team
28 Clinical Genetics Department
29 Yorkshire Regional Genetics Service
30 Ferguson-Smith Centre for Clinical Genetics
31 Wessex Clinical Genetics Service
32 West Midlands Regional Genetics Service
33 Sheffield Clinical Genetics Service
34 Abramson Cancer Center
35 Division of Special Gynecology
36 Women's Cancer Program
37 Department of Obstetrics and Gynecology
38 Department of Pathology
39 Section of Genetic Oncology
40 Department of Oncology
41 Department of Clinical Genetics
42 Department of Oncology
43 Department of Oncology
44 Department of Radiation Sciences and Oncology
Zachary Fredericksen
- Function : Author
- PersonId : 909923
Sophie Giraud
- Function : Author
- PersonId : 909729
Sylvie Mazoyer
- Function : Author
- PersonId : 752568
- IdHAL : sylvie-mazoyer
- ORCID : 0000-0002-2135-0160
- IdRef : 075600390
Barbara Wappenschmidt
- Function : Author
- PersonId : 908385
Christoph Engel
- Function : Author
- PersonId : 910041
Peter Devilee
- Function : Author
- PersonId : 910049
Patricia Harrington
- Function : Author
- PersonId : 910054
Olga Sinilnikova
- Function : Author
- PersonId : 910067
Georgia Chenevix-Trench
- Function : Author
- PersonId : 909943
Amanda Spurdle
Connectez-vous pour contacter l'auteur
- Function : Correspondent author
- PersonId : 910068
Connectez-vous pour contacter l'auteur
Abstract
INTRODUCTION: Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. METHODS: We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. RESULTS: SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r² = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P(trend) = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P(trend) = 0.018). CONCLUSIONS: This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
Domains
Cancer
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