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

Varadi, Verena; Bevier, Melanie; Grzybowska, Ewa; Johansson, Robert; Enquist, Kerstin; Henriksson, Roger; Butkiewicz, Dorota; Pamula-Pilat, Jolanta; Tecza, Karolina and Hemminki, Kari LU , et al. (2011) In Breast Cancer Research and Treatment 129(1). p.235-245
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 beta, delta, theta and zeta (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... (More)
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 beta, delta, theta and zeta (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 zeta 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 zeta subunit genes regarding the development and progression of BC. (Less)
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organization
publishing date
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Contribution to journal
publication status
published
subject
keywords
Breast cancer, SNPs, Chromosomal instability, Polymerases, Prognostic, marker
in
Breast Cancer Research and Treatment
volume
129
issue
1
pages
235 - 245
publisher
Springer
external identifiers
  • wos:000292878700025
  • scopus:79960845296
ISSN
1573-7217
DOI
10.1007/s10549-011-1460-z
language
English
LU publication?
yes
id
dced8009-5f7c-4e50-a4dc-c340bc74b442 (old id 2092712)
date added to LUP
2011-09-02 08:34:30
date last changed
2017-07-23 04:25:45
@article{dced8009-5f7c-4e50-a4dc-c340bc74b442,
  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 beta, delta, theta and zeta (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 zeta 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 zeta subunit genes regarding the development and progression of BC.},
  author       = {Varadi, Verena and Bevier, Melanie and Grzybowska, Ewa and Johansson, Robert and Enquist, Kerstin and Henriksson, Roger and Butkiewicz, Dorota and Pamula-Pilat, Jolanta and Tecza, Karolina and Hemminki, Kari and Lenner, Per and Försti, Asta},
  issn         = {1573-7217},
  keyword      = {Breast cancer,SNPs,Chromosomal instability,Polymerases,Prognostic,marker},
  language     = {eng},
  number       = {1},
  pages        = {235--245},
  publisher    = {Springer},
  series       = {Breast Cancer Research and Treatment},
  title        = {Genetic variation in genes encoding for polymerase zeta subunits associates with breast cancer risk, tumour characteristics and survival},
  url          = {http://dx.doi.org/10.1007/s10549-011-1460-z},
  volume       = {129},
  year         = {2011},
}