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Genetic variation in genes encoding for polymerase ζ subunits associates with breast cancer risk, tumour characteristics and survival

  • Epidemiology
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Abstract

Chromosomal instability is a known hallmark of many cancers. DNA polymerases represent a group of enzymes that are involved in the mechanism of chromosomal instability as they have a central function in DNA metabolism. We hypothesized that genetic variation in the polymerase genes may affect gene expression or protein configuration and by that cancer risk and clinical outcome. We selected four genes encoding for the catalytic subunits of the polymerases β, δ, θ and ζ (POLB, POLD1, POLQ and REV3L, respectively) and two associated proteins (MAD2L2 and REV1) because of their previously reported association with chromosomal instability and/or tumorigenesis. We selected potentially functional and most informative tagging single nucleotide polymorphisms (SNPs) for genotyping in a population-based series of 783 Swedish breast cancer (BC) cases and 1562 controls. SNPs that showed a significant association in the Swedish population were additionally genotyped in a Polish population consisting of 506 familial/early onset BC cases and 568 controls. SNPs in all three polymerase ζ subunit genes associated either with BC risk or prognosis. Two SNPs in REV3L and one SNP in MAD2L2 associated with BC risk: rs462779 (multiplicative model: OR 0.79, 95% CI 0.68–0.92), rs3204953 (dominant model: OR 1.28, 95% CI 1.05–1.56) and rs2233004 (recessive model: OR 0.49, 95% CI 0.28–0.86). Homozygous carriers of the minor allele C of the third SNP in REV3L, rs11153292, had significantly worse survival compared to the TT genotype carriers (HR 2.93, 95% CI 1.34–6.44). Minor allele carriers of two REV1 SNPs (rs6761391 and rs3792142) had significantly more often large tumours and tumours with high histological grade and stage. No association was observed for SNPs in POLB, POLQ and POLD1. Altogether, our data suggest a significant role of genetic variation in the polymerase ζ subunit genes regarding the development and progression of BC.

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Acknowledgments

We thank Asa Agren (Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Sweden) for her efficiency and skill in keeping track of samples and data. The Northern Sweden Breast Cancer Group is appreciated for providing the clinical data.

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Authors and Affiliations

  1. Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany

    Verena Varadi, Melanie Bevier, Kari Hemminki & Asta Försti

  2. Center for Translational Research and Molecular Biology of Cancer, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland

    Ewa Grzybowska, Dorota Butkiewicz, Jolanta Pamula-Pilat & Karolina Tecza

  3. Department of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden

    Robert Johansson, Roger Henriksson & Per Lenner

  4. Department of Public Health and Clinical Medicine/Nutritional Research, Umeå University, Umeå, Sweden

    Kerstin Enquist

  5. Department of Oncology, Karolinska University Hospital, Stockholm, Sweden

    Roger Henriksson

  6. Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden

    Kari Hemminki & Asta Försti

Authors
  1. Verena Varadi
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  2. Melanie Bevier
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  8. Jolanta Pamula-Pilat
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  11. Per Lenner
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  12. Asta Försti
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Correspondence to Verena Varadi.

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Varadi, V., Bevier, M., Grzybowska, E. et al. Genetic variation in genes encoding for polymerase ζ subunits associates with breast cancer risk, tumour characteristics and survival. Breast Cancer Res Treat 129, 235–245 (2011). https://doi.org/10.1007/s10549-011-1460-z

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  • DOI: https://doi.org/10.1007/s10549-011-1460-z

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