title: 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.
authors: German Cancer Research Center, Im Neuenheimer Feld 580, 69120, Heidelberg, Germany. v.varadi@dkfz-heidelberg.de
authors: Verena
authors: V
authors: Varadi
authors: Melanie
authors: M
authors: Bevier
authors: Ewa
authors: E
authors: Grzybowska
authors: Robert
authors: R
authors: Johansson
authors: Kerstin
authors: K
authors: Enquist
authors: Roger
authors: R
authors: Henriksson
authors: Dorota
authors: D
authors: Butkiewicz
authors: Jolanta
authors: J
authors: Pamula-Pilat
authors: Karolina
authors: K
authors: Tecza
authors: Kari
authors: K
authors: Hemminki
authors: Per
authors: P
authors: Lenner
authors: Asta
authors: A
authors: Försti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D064246:Mad2 Proteins; D008875:Middle Aged; D009367:Neoplasm Staging; D011044:Poland; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011506:Proteins / Q000235:genetics; D012306:Risk; D016019:Survival Analysis; D013548:Sweden; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C120552:MAD2L2 protein, human; D064246:Mad2 Proteins; D011506:Proteins; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human