Germline variants of base excision repair genes and breast cancer: A polymorphism in DNA polymerase gamma modifies gene expression and breast cancer risk.
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Germline variants of base excision repair genes and breast cancer: A polymorphism in DNA polymerase gamma modifies gene expression and breast cancer risk. / Popanda, Odilia; Seibold, Petra; Nikolov, Ivaylo; Oakes, Christopher C; Burwinkel, Barbara; Hausmann, Sebastian; Flesch-Janys, Dieter; Plass, Christoph; Chang-Claude, Jenny; Schmezer, Peter.
in: INT J CANCER, Jahrgang 132, Nr. 1, 1, 2013, S. 55-62.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Germline variants of base excision repair genes and breast cancer: A polymorphism in DNA polymerase gamma modifies gene expression and breast cancer risk.
AU - Popanda, Odilia
AU - Seibold, Petra
AU - Nikolov, Ivaylo
AU - Oakes, Christopher C
AU - Burwinkel, Barbara
AU - Hausmann, Sebastian
AU - Flesch-Janys, Dieter
AU - Plass, Christoph
AU - Chang-Claude, Jenny
AU - Schmezer, Peter
PY - 2013
Y1 - 2013
N2 - Base excision repair (BER) removes DNA damage induced by endogenous reactive oxygen species or ionizing radiation, important breast cancer risk factors. Genetic variation associated with impaired BER might thus increase breast cancer risk. Therefore, we assessed risk associations of 123 common single nucleotide polymorphisms (SNPs) in 19 BER genes in 1,639 postmenopausal breast cancer cases and 1,967 controls from the German population-based case-control study MARIE. SNPs were tagging SNPs representing genetic variation across the gene together with potentially functional SNPs. Risk associations were assessed using conditional logistic regression, adjusted for potential breast cancer risk factors. Significant associations between polymorphisms and breast cancer risk were found for one SNP in PARP2 and three SNPs in the mitochondrial DNA polymerase gamma, POLG. A SNP in the promoter region of POLG (rs2856268, A>G) showed a protective effect for homozygous GG carriers (odds ratio 0.81, 95% confidence intervals 0.65-1.00). Joint analysis of an enlarged sample set and haplotype analysis supported the results for POLG. Quantification of POLG mRNA expression in lymphocytes of 148 breast cancer patients revealed higher mRNA levels for rs2856268 GG carriers (p value = 0.038). A luciferase promoter assay showed significant differences between constructs harboring the respective alleles. Taken together, our results suggest that genetic variation in the POLG promoter region affects DNA polymerase gamma levels in mitochondria. This could contribute to the reported increase in mitochondrial mutation frequency resulting in dysfunction and altered breast cancer risk. Risk effects and the functional impact of the POLG promoter variant require further confirmation.
AB - Base excision repair (BER) removes DNA damage induced by endogenous reactive oxygen species or ionizing radiation, important breast cancer risk factors. Genetic variation associated with impaired BER might thus increase breast cancer risk. Therefore, we assessed risk associations of 123 common single nucleotide polymorphisms (SNPs) in 19 BER genes in 1,639 postmenopausal breast cancer cases and 1,967 controls from the German population-based case-control study MARIE. SNPs were tagging SNPs representing genetic variation across the gene together with potentially functional SNPs. Risk associations were assessed using conditional logistic regression, adjusted for potential breast cancer risk factors. Significant associations between polymorphisms and breast cancer risk were found for one SNP in PARP2 and three SNPs in the mitochondrial DNA polymerase gamma, POLG. A SNP in the promoter region of POLG (rs2856268, A>G) showed a protective effect for homozygous GG carriers (odds ratio 0.81, 95% confidence intervals 0.65-1.00). Joint analysis of an enlarged sample set and haplotype analysis supported the results for POLG. Quantification of POLG mRNA expression in lymphocytes of 148 breast cancer patients revealed higher mRNA levels for rs2856268 GG carriers (p value = 0.038). A luciferase promoter assay showed significant differences between constructs harboring the respective alleles. Taken together, our results suggest that genetic variation in the POLG promoter region affects DNA polymerase gamma levels in mitochondria. This could contribute to the reported increase in mitochondrial mutation frequency resulting in dysfunction and altered breast cancer risk. Risk effects and the functional impact of the POLG promoter variant require further confirmation.
KW - Humans
KW - Aged
KW - Female
KW - Middle Aged
KW - Risk Factors
KW - Logistic Models
KW - Genetic Predisposition to Disease
KW - Gene Expression
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Case-Control Studies
KW - Breast Neoplasms/genetics
KW - DNA Repair
KW - DNA-Directed DNA Polymerase/genetics
KW - Germ-Line Mutation
KW - Lymphocytes/physiology
KW - Mitochondria/genetics
KW - Poly(ADP-ribose) Polymerases/genetics
KW - Postmenopause/genetics
KW - Humans
KW - Aged
KW - Female
KW - Middle Aged
KW - Risk Factors
KW - Logistic Models
KW - Genetic Predisposition to Disease
KW - Gene Expression
KW - Polymorphism, Single Nucleotide
KW - Promoter Regions, Genetic
KW - Case-Control Studies
KW - Breast Neoplasms/genetics
KW - DNA Repair
KW - DNA-Directed DNA Polymerase/genetics
KW - Germ-Line Mutation
KW - Lymphocytes/physiology
KW - Mitochondria/genetics
KW - Poly(ADP-ribose) Polymerases/genetics
KW - Postmenopause/genetics
M3 - SCORING: Journal article
VL - 132
SP - 55
EP - 62
JO - INT J CANCER
JF - INT J CANCER
SN - 0020-7136
IS - 1
M1 - 1
ER -
