Journal articles

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

* Corresponding author

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

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.

Document type :

Journal articles

Domain :

Life Sciences [q-bio] / Cancer

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https://www.hal.inserm.fr/inserm-00622882
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Submitted on : Tuesday, September 13, 2011 - 7:01:10 AM
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