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

Verena Varadi (1) , Melanie Bevier (1) , Ewa Grzybowska (2) , Robert Johansson (3) , Kerstin Enquist (4) , Roger Henriksson (3, 5) , Dorota Butkiewicz (2) , Jolanta Pamula-Pilat (2) , Karolina Tecza (2) , Kari Hemminki (1, 6) , Per Lenner (3) , Asta Försti (1, 6)

1 Division of Molecular Genetic Epidemiology
2 Center for Translational Research and Molecular Biology of Cancer
3 Department of Radiation Sciences, Oncology
4 Department of Public Health and Clinical Medicine/Nutritional Research
5 Department of Oncology
6 Center for Primary Health Care Research, Clinical Research Center

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 ( and respectively) and two associated proteins ( and ) 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 and one SNP in 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 , 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 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 , and . Altogether, our data suggest a significant role of genetic variation in the polymerase ζ subunit genes regarding the development and progression of BC.

Mots clés: Breast cancer; SNPs; Chromosomal instability; Polymerases; Prognostic marker

Verena Varadi, Melanie Bevier, Ewa Grzybowska, Robert Johansson, Kerstin Enquist, et al.. Genetic variation in genes encoding for polymerase ζ subunits associates with breast cancer risk, tumour characteristics and survival. Breast Cancer Research and Treatment, 2011, 129 (1), pp.235-245. ⟨10.1007/s10549-011-1460-z⟩. ⟨hal-00628285⟩