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Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer

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Abstract

Mitotic regulatory pathways insure proper timing of mitotic entry, sister chromatid cohesion and separation, and cytokinesis. Disruption of this process results in inappropriate chromosome segregation and aneuploidy, and appears to contribute to cancer. Specifically, disregulation and somatic mutation of mitotic regulators has been observed in human cancers, and overexpression of mitotic regulators is common in aggressive and late stage tumors. However, the role of germline variation in mitotic pathways and risk of cancer is not well understood. We tested 1,084 haplotype-tagging and functional variants from 164 genes in mitotic regulatory pathways in 791 Caucasian women with breast cancer and 843 healthy controls for association with risk of overall and high grade breast cancer. Sixty-one single nucleotide polymorphisms (SNPs) from 40 genes were associated (P < 0.05) with risk of breast cancer in a log-additive model. In addition, 60 SNPs were associated (P < 0.05) with risk of high grade breast cancer. However, none of these associations were significant after Bonferroni correction for multiple testing. In gene-level analyses, CDC25C, SCC1/RAD21, TLK2, and SMC6L1 were associated (P < 0.05) with overall breast cancer risk, CDC6, CDC27, SUMO3, RASSF1, KIF2, and CDC14A were associated with high grade breast cancer risk, and EIF3S10 and CDC25A were associated with both. Further investigation in breast and other cancers are needed to understand the influence of inherited variation in mitotic genes on tumor grade and cancer risk.

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Acknowledgments

This study was supported by the NIH grant CA122340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer, CA116201. KNS is a Mayo Cancer Genetic Epidemiology Training Program (CA92049-03) fellow.

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Authors and Affiliations

  1. Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA

    Kristen N. Stevens, Zachary Fredericksen, V. Shane Pankratz, James Cerhan, Celine M. Vachon & Janet E. Olson

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Stabile 2-42, 200 First Street SW, Rochester, MN, 55905, USA

    Xianshu Wang & Fergus J. Couch

Authors
  1. Kristen N. Stevens
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  2. Xianshu Wang
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  3. Zachary Fredericksen
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  4. V. Shane Pankratz
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  5. James Cerhan
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  6. Celine M. Vachon
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  7. Janet E. Olson
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  8. Fergus J. Couch
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Corresponding author

Correspondence to Fergus J. Couch.

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Stevens, K.N., Wang, X., Fredericksen, Z. et al. Evaluation of associations between common variation in mitotic regulatory pathways and risk of overall and high grade breast cancer. Breast Cancer Res Treat 129, 617–622 (2011). https://doi.org/10.1007/s10549-011-1587-y

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  • DOI: https://doi.org/10.1007/s10549-011-1587-y

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