Abstract
DNA polymerase β (Polβ) provides most of the gap-filling synthesis at apurinic/apyrimidine sites of damaged DNA in the base excision repair pathway. Mutations in the gene encoding DNA polβ have been identified in various carcinomas. We performed a case–control study to test the association between two polymorphisms in the polβ gene: a Pro → Arg change at codon 242 (the Pro242Arg polymorphism) and a Lys → Met change at codon 289 (the Lys289Met polymorphism) and breast cancer risk and cancer progression. Genotypes were determined in DNA from peripheral blood lymphocytes of 150 breast cancer patients and 150 cancer-free, age-matched women (controls) by PCR-RFLP. A strong association between breast cancer occurrence and the Met/Met phenotype of the Lys289Met polymorphism [odds ratio (OR) 3.67; 95% confidence interval (CI) 1.87–7.56] and the Pro/Arg phenotype of the Pro242Lys polymorphism (OR 1.96; 95% CI 1.15–3.34) was found. Polymorphism–polymorphism interaction between the Met/Met phenotype of the Lys289Met and the Pro/Arg phenotype of the Pro242Arg variants increased the risk of breast cancer (OR 3.05; 95% CI 1.31–7.09). We did not observe any correlation between studied polymorphisms and breast cancer progression evaluated by node-metastasis, tumor size and Bloom–Richardson grading. In conclusion, Polβ may play a role in the breast carcinogenesis and the Lys289Met polymorphism of the polβ gene may be considered as an independent, early, molecular diagnostic marker in breast cancer. The Pro242Arg polymorphism may contribute to the carcinogenesis through the interaction with the Lys289Met and therefore may be regarded as a dependent, auxiliary marker.
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Dufloth RM, Costa S, Schmitt F, Zeferino LC (2005) DNA repair gene polymorphisms and susceptibility to familial breast cancer in a group of patients from Campinas, Brazil. Genet Mol Res 4:771–782
Garcia-Closas M, Egan KM, Newcomb PA, Brinton LA, Titus-Ernstoff L, Chanock S, Welch R, Lissowska J, Peplonska B, Szeszenia-Dabrowska N, Zatonski W, Bardin-Mikolajczak A, Struewing JP (2006) Polymorphisms in DNA double-strand break repair genes and risk of breast cancer: two population-based studies in USA and Poland, and meta-analyses. Hum Genet 119:376–388
Han S, Zhang HT, Wang Z, Xie Y, Tang R, Mao Y, Li Y (2006) DNA repair gene XRCC3 polymorphisms and cancer risk: a meta-analysis of 48 case–control studies. Eur J Hum Genet [Epub ahead of print]
Zhang Y, Newcomb PA, Egan KM, Titus-Ernstoff L, Chanock S, Welch R, Brinton LA, Lissowska J, Bardin-Mikolajczak A, Peplonska B, Szeszenia-Dabrowska N, Zatonski W, Garcia-Closas M (2006) Genetic polymorphisms in base-excision repair pathway genes and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 15:353–358
Poplawski T, Zadrozny M, Kolacinska A, Rykala J, Morawiec Z, Blasiak J (2005) Polymorphisms of the DNA mismatch repair gene HMSH2 in breast cancer occurrence and progression. Breast Cancer Res Treat 94:199–204
Sliwinski T, Krupa R, Majsterek I, Rykala J, Kolacinska A, Morawiec Z, Drzewoski J, Zadrozny M, Blasiak J (2005) Polymorphisms of the BRCA2 and RAD51 genes in breast cancer. Breast Cancer Res Treat 94:105–109
Lindahl T (2001) Keynote: past, present, and future aspects of base excision repair. Prog Nucleic Acid Res Mol Biol 68:xvii–xxx
Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715
Idriss HT, Al-Assar O, Wilson SH (2002) DNA polymerase beta. Int J Biochem Cell Biol 34:321–324
Wilson SH, Singhal RK (1998) Mammalian DNA repair and the cellular DNA polymerases. In: Nickoloff JA, Hoekstra MF (eds) DNA damage and repair. Humana, Clifton, pp. 161–180
Sobol RW, Prasad R, Evenski A, Baker A, Yang XP, Horton JK, Wilson SH (2000) The lyase activity of the DNA repair protein beta-polymerase protects from DNA-damage-induced cytotoxicity. Nature 405:807–810
Matsumoto Y, Kim K (1995) Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science 269:699–702
Frosina G, Fortini P, Rossi O, Carrozzino F, Raspaglio G, Cox LS, Lane DP, Abbondandolo A, Dogliotti E (1996) Two pathways for base excision repair in mammalian cells. J Biol Chem 271:9573–9578
Kosa JL, Sweasy JB (1999) The E249K mutator mutant of DNA polymerase beta extends mispaired termini. J Biol Chem 274:35866–35872
Maitra M, Gudzelak A, Jr, Li SX, Matsumoto Y, Eckert KA, Jager J, Sweasy JB (2002) Threonine 79 is a hinge residue that governs the fidelity of DNA polymerase beta by helping to position the DNA within the active site. J Biol Chem 277:35550–35560
Shah AM, Li SX, Anderson KS, Sweasy JB (2001) Y265H mutator mutant of DNA polymerase beta. Proper teometric alignment is critical for fidelity. J Biol Chem 276:10824–10831
Beard WA, Osheroff WP, Prasad R, Sawaya MR, Jaju M, Wood TG, Kraut J, Kunkel TA, Wilson SH (1996) Enzyme–DNA interactions required for efficient nucleotide incorporation and discrimination in human DNA polymerase beta. J Biol Chem 271:12141–12144
Osheroff WP, Beard WA, Yin S, Wilson SH, Kunkel TA (2000) Minor groove interactions at the DNA polymerase beta active site modulate single-base deletion error rates. J Biol Chem 275:28033–28038
Sweasy JB, Loeb L (1993) Detection and characterization of mammalian DNA polymerase β mutants by functional complementation in Escherichia coli. Proc Natl Acad Sci USA 90:4626–4630
Ali-Osman F, Berger MS, Rairkar A, Stein DE (1994) Enhanced repair of a cisplatin damaged reporter chloramphenicol-O-acetyltransferase gene and altered activities of DNA polymerases α and β, and DNA ligase in cells of a human malignant glioma following in vivo cisplatin therapy. J Cell Biochem 54:11–19
Plug AW, Clairmont CA, Sapi E, Ashley T, Sweasy JB (1997) Evidence for a role for DNA polymerase β in mammalian meiosis. Proc Natl Acad Sci USA 94:1327–1331
Miscia S, Di Baldassarre A, Alba Rana R, Di Peitro R, Cataldi A (1997) Engagement of DNA polymerases during apoptosis. Cell Prolif 30:325–340
Loeb LA (1998) Cancer cells exhibit a mutator phenotype. Adv Cancer Res 72:25–56
Shadan F, Villarreal L (1996) Potential role of DNA polymerase beta in gene therapy against cancer: a case for colorectal cancer. Med Hypotheses 47:1–9
Dobashi Y, Shuin T, Tsuruga H, Uemura H, Torigoe S, Kubota Y (1994) DNA polymerase beta gene mutation in human prostate cancer. Cancer Res 54:2827–2829
Iwanaga A, Ouchida M, Miyazaki K, Hori K, Mukai T (1999) Functional mutation of DNA polymerase beta found in human gastric cancer-inability of the base excision repair in vitro. Mutat Res 435:121–128
Wang L, Patel U, Ghosh L, Banerjee S (1992) DNA polymerase beta mutations in human colorectal cancer. Cancer Res 52:4824–4827
Kubota Y, Murakami-Murofushi K, Shimada Y, Ogiu T, Oikawa T (1995) Reduced fidelity of DNA synthesis in cell extracts from chemically induced primary thymic lymphomas of mice. Cancer Res 55:3777–3780
Bhattacharyya N, Chen HC, Grundfest-Broniatowski S, Banerjee S (1999) Alteration of hMSH2 and DNA polymerase beta genes in breast carcinomas and fibroadenomas. Biochem Biophys Res Commun 259:429–435
Wang L, Banerjee S (1995) Mutations in DNA polymerase β occur in breast, prostate, and colorectal cancer. Int J Oncol 6:459–463
Bhattacharyya N, Chen HC, Comhair S, Erzurum SC, Banerjee S (1999) Variant forms of DNA polymerase beta in primary lung carcinomas. DNA Cell Biol 8:549–554
Kang D (2003) Genetic polymorphisms and cancer susceptibility in Korean women. J Biochem Mol Biol 36:28–34
Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11:1513–1530
Onay VU, Briollais L, Knight JA, Shi E, Wang Y, Wells S, Li H, Rajendram I, Andrulis IL, Ozcelik H (2006) SNP–SNP interactions in breast cancer susceptibility. BMC Cancer 6:114
Lippke JA, Strzempko MN, Raia FF, Simon SL, French CK (1987) Isolation of intact high-molecular-weight DNA by using guanidine isothiocyanate. Appl Environ Microbiol 53:2588–2589
Lang T, Maitra M, Starcevic D, Li SX, Sweasy JB (2004) A DNA polymerase beta mutant from colon cancer cells induces mutations. Proc Natl Acad Sci USA 101:6074–6079
Macoska JA, Trybus TM, Sakr WA, Wolf MC, Benson PD, Powell IJ, Pontes JE (1994) Fluorescence in situ hybridization analysis of 8p allelic loss and chromosome 8 instability in human prostate cancer. Cancer Res 54:3824–3830
Srivastava DK, Husain I, Arteaga CL, Wilson SH (1999) DNA polymerase beta expression differences in selected human tumors and cell lines. Carcinogenesis 20:1049–1054
Blasiak J, Arabski M, Krupa R, Wozniak K, Rykala J, Kolacinska A, Morawiec Z, Drzewoski J, Zadrozny M (2004) Basal, oxidative and alkylative DNA damage, DNA repair efficacy and mutagen sensitivity in breast cancer. Mutat Res 554:139–148
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This work was supported by grants 505/363 (JB) and 505/396 (TS) from the University of Lodz and “Spoleczny Komitet Walki z Rakiem” Foundation.
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Sliwinski, T., Ziemba, P., Morawiec, Z. et al. Polymorphisms of the DNA polymerase β gene in breast cancer. Breast Cancer Res Treat 103, 161–166 (2007). https://doi.org/10.1007/s10549-006-9357-y
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DOI: https://doi.org/10.1007/s10549-006-9357-y