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Association of genetic variation in mitotic kinases with breast cancer risk

  • Xianshu Wang
  • Zachary S. Fredericksen
  • Robert A. Vierkant
  • Matthew L. Kosel
  • V. Shane Pankratz
  • James R. Cerhan
  • Christina Justenhoven
  • Hiltrud Brauch
  • GENICA Consortium
  • Janet E. Olson
  • Fergus J. CouchEmail author
Epidemiology

Abstract

An RNAi-based functional screening of mitotic kinases in Drosophila recently identified a number of members of the kinome that are required for normal cell division. Depletion of these kinases resulted in a number of different mitotic abnormalities including spindle malformation, chromosome mis-segregation, centrosome amplification and failure of cytokinesis (Bettencourt-Dias et al. in Nature 432:980–987, 2004). Since mitotic defects are commonly observed in cancer cells, these kinases may contribute to tumor development and/or progression. To investigate whether common genetic variation in the mitotic kinases are associated with breast cancer risk, we genotyped 386 single nucleotide polymorphisms (SNPs) from 44 mitotic kinase genes, in 798 breast cancer cases and 843 unaffected controls from a clinic-based study. A total of 22 SNPs from 13 kinase genes displayed significant associations with breast cancer risk (P trend ≤ 0.05), including two SNPs from FYN (rs6914091 and rs1465061) that remained of interest after accounting for multiple testing (q = 0.06). These associations were stronger when evaluating cases with estrogen and progesterone receptor positive tumors. In addition, haplotype-based tests identified significant associations with risk for common haplotypes of the MAST2 (P = 0.04) and MAP2K4 (P = 0.006) genes. Although requiring replication, these findings suggest that genetic polymorphisms in mitotic kinases that have been implicated in chromosome instability and aneuploidy may contribute to the development of breast cancer.

Keywords

Mitosis Mitotic kinase Single nucleotide polymorphism (SNP) Haplotype Breast cancer risk 

Notes

Acknowledgments

This study was funded in part by a grant 5R01CA122340-02 and a Breast Cancer Specialized Program of Research Excellence (SPORE) grant P50CA166201 from the National Cancer Institute. J. C. and H. B. are supported by the Federal Ministry of Education and Research Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, and 01KW0114 and the Robert Bosch Foundation of Medical Research, Stuttgart, Deutsches Krebsforschungszentrum, Heidelberg, Berufsgenossenschaftliches Forschungsinstitut für Arbeitsmedizin Bochum, and Medizinische Universitäts-und Poliklinik, Bonn, Germany (GENICA study); and the Deutsche Krebshilfe (GESBC study).

Supplementary material

10549_2009_404_MOESM1_ESM.pdf (98 kb)
Supplementary material 1 (PDF 97 kb)

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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Xianshu Wang
    • 1
  • Zachary S. Fredericksen
    • 2
  • Robert A. Vierkant
    • 2
  • Matthew L. Kosel
    • 2
  • V. Shane Pankratz
    • 2
  • James R. Cerhan
    • 2
  • Christina Justenhoven
    • 3
  • Hiltrud Brauch
    • 3
  • GENICA Consortium
  • Janet E. Olson
    • 2
  • Fergus J. Couch
    • 1
    • 2
    Email author
  1. 1.Department of Laboratory Medicine and PathologyMayo Clinic College of MedicineRochesterUSA
  2. 2.Health Sciences ResearchMayo Clinic College of MedicineRochesterUSA
  3. 3.Dr. Margarete Fischer-Bosch Institut fur Klinische PharmakologieUniversity of TübingenStuttgartGermany

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