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

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.

journal_name

Breast Cancer Res Treat

journal_title

Breast cancer research and treatment

authors

Varadi V,Bevier M,Grzybowska E,Johansson R,Enquist K,Henriksson R,Butkiewicz D,Pamula-Pilat J,Tecza K,Hemminki K,Lenner P,Försti A

doi

10.1007/s10549-011-1460-z

subject

Has Abstract

pub_date

2011-08-01 00:00:00

pages

235-45

issue

eissn

0167-6806

issn

1573-7217

journal_volume

129

pub_type

杂志文章

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