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Evidence for SMAD3 as a modifier of breast cancer risk in BRCA2 mutation carriers

Walker, L. C., Fredericksen, Z. S., Wang, X., Tarrell, R., Pankratz, V. S., Lindor, N. M., Beesley, J., Healey, S., Chen, X., Fab, K. C., Stoppa-Lyonnet, D., Tirapo, C., Giraud, S., Mazoyer, S., Muller, D., Fricker, J-P., Delnatte, C., Schmutzler, R. K., Wappenschmidt, B., Engel, C., Schoenbuchner, I., Deissler, H., Meindl, A., Hogervorst, F. B., Verheus, M., Hooning, M. J., van den Ouweland, A. M. W., Nelen, M. R., Ausems, M. G. E. M., Aalfs, C. M., van Asperen, C. J., Devilee, P., Gerrits, M. M., Waisfisz, Q., Szabo, C. I., Quad, M. S., Easton, D. F., Peock, S., Cook, M., Oliver, C. T., Frost, D., Harrington, P., Evans, D. G., Lalloo, F., Eeles, R., Izatt, L., Chu, C., Davidson, R., Eccles, D., Ong, K-R., GEMO Study Collaborators, HEBON, EMBRACE & SWE-BRCA, 2010, In : Breast cancer research. 12, 6, 10 p., 102.

Research output: Contribution to journalArticleAcademicpeer-review

  • Logan C. Walker
  • Zachary S. Fredericksen
  • Xianshu Wang
  • Robert Tarrell
  • Vernon S. Pankratz
  • Noralane M. Lindor
  • Jonathan Beesley
  • Sue Healey
  • Xiaoqing Chen
  • K. Con Fab
  • Dominique Stoppa-Lyonnet
  • Carole Tirapo
  • Sophie Giraud
  • Sylvie Mazoyer
  • Daniele Muller
  • Jean-Pierre Fricker
  • Capucine Delnatte
  • Rita K. Schmutzler
  • Barbara Wappenschmidt
  • Christoph Engel
  • Ines Schoenbuchner
  • Helmut Deissler
  • Alfons Meindl
  • Frans B. Hogervorst
  • Martijn Verheus
  • Maartje J. Hooning
  • Ans M. W. van den Ouweland
  • Marcel R. Nelen
  • Margreet G. E. M. Ausems
  • Cora M. Aalfs
  • Christi J. van Asperen
  • Peter Devilee
  • Monique M. Gerrits
  • Quinten Waisfisz
  • Csilla I. Szabo
  • Mod S. Quad
  • Douglas F. Easton
  • Susan Peock
  • Margaret Cook
  • Clare T. Oliver
  • Debra Frost
  • Patricia Harrington
  • D. Gareth Evans
  • Fiona Lalloo
  • Ros Eeles
  • Louise Izatt
  • Carol Chu
  • Rosemarie Davidson
  • Diana Eccles
  • Kai-Ren Ong
  • GEMO Study Collaborators
  • HEBON
  • EMBRACE
  • SWE-BRCA

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 (r(2) = 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.

Original languageEnglish
Article number102
Number of pages10
JournalBreast cancer research
Volume12
Issue number6
Publication statusPublished - 2010

    Keywords

  • GENOME-WIDE ASSOCIATION, OVARIAN-CANCER, PROPHYLACTIC OOPHORECTOMY, INVESTIGATORS, POLYMORPHISM, POPULATION, CONSORTIUM, ALLELES, COHORT, GENES

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