Carcinogenesis, Vol. 22, No. 9, 1437-1445,
September 2001
© 2001 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects
1 Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, 10126, Torino,
2 ISI Foundation, Institute for Scientific Interchange, Villa Gualino, 10133, Torino,
3 Unità di Epidemiologia, CSPO, 50135, Firenze,
4 Servizio di Oncologia Sperimentale, Istituto Nazionale per la Ricerca sul Cancro (IST), 16132, Genova,
5 Servizio di Epidemiologia, Istituto Nazionale Tumori, 80131, Napoli,
6 Unità di Epidemiologia, Istituto Nazionale Tumori, 20100, Milano,
7 Registro Tumori–Azienda Ospedaliera `Civile–M.P. Arezzo', 97100, Ragusa and
8 Unità di Epidemiologia dei Tumori, Dipartimento di Scienze Biomediche e Oncologia Umana, Via Santena 7, 10126, Torino, Italy
DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by 32P-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and XPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 109 normal nucleotides by DNA 32P-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR–RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes had an average DNA adduct level of 11.44 ± 1.48 (±SE) compared with 7.69 ± 0.88 in Thr/Met heterozygotes and 6.94 ± 1.11 in Thr/Thr homozygotes (F = 3.206, P = 0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 ± 5.42 compared with 6.16 ± 0.97 in Gln/Arg heterozygotes and 6.78 ± 1.10 in Arg/Arg homozygotes (F = 5.237, P = 0.007). A significant odds ratio (3.81, 95% CI 1.02–14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and suggest a need for further investigation into the possible interactions between these polymorphisms, smoking and other risk factors.
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M. R. Spitz, Q. Wei, Q. Dong, C. I. Amos, and X. Wu Genetic Susceptibility to Lung Cancer: The Role of DNA Damage and Repair Cancer Epidemiol. Biomarkers Prev., August 1, 2003; 12(8): 689 - 698. [Full Text] [PDF]
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P. P. Medina, S. A. Ahrendt, M. Pollan, P. Fernandez, D. Sidransky, and M. Sanchez-Cespedes Screening of Homologous Recombination Gene Polymorphisms in Lung Cancer Patients Reveals an Association of the NBS1-185Gln Variant and p53 Gene Mutations Cancer Epidemiol. Biomarkers Prev., August 1, 2003; 12(8): 699 - 704. [Abstract] [Full Text] [PDF]
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G. Matullo, M. Peluso, S. Polidoro, S. Guarrera, A. Munnia, V. Krogh, G. Masala, F. Berrino, S. Panico, R. Tumino, et al. Combination of DNA Repair Gene Single Nucleotide Polymorphisms and Increased Levels of DNA Adducts in a Population-based Study Cancer Epidemiol. Biomarkers Prev., July 1, 2003; 12(7): 674 - 677. [Abstract] [Full Text] [PDF]
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W. Zhou, G. Liu, D. P. Miller, S. W. Thurston, L. L. Xu, J. C. Wain, T. J. Lynch, L. Su, and D. C. Christiani Polymorphisms in the DNA Repair Genes XRCC1 and ERCC2, Smoking, and Lung Cancer Risk Cancer Epidemiol. Biomarkers Prev., April 1, 2003; 12(4): 359 - 365. [Abstract] [Full Text] [PDF]
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F. Veglia, G. Matullo, and P. Vineis Bulky DNA Adducts and Risk of Cancer: A Meta-Analysis Cancer Epidemiol. Biomarkers Prev., February 1, 2003; 12(2): 157 - 160. [Abstract] [Full Text] [PDF]
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E. L. Goode, C. M. Ulrich, and J. D. Potter Polymorphisms in DNA Repair Genes and Associations with Cancer Risk Cancer Epidemiol. Biomarkers Prev., December 1, 2002; 11(12): 1513 - 1530. [Abstract] [Full Text] [PDF]
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D. H. Phillips Smoking-related DNA and protein adducts in human tissues Carcinogenesis, December 1, 2002; 23(12): 1979 - 2004. [Abstract] [Full Text] [PDF]
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C. Seedhouse, R. Bainton, M. Lewis, A. Harding, N. Russell, and E. Das-Gupta The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia Blood, November 15, 2002; 100(10): 3761 - 3766. [Abstract] [Full Text] [PDF]
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Z. Duan, H. Shen, J. E. Lee, J. E. Gershenwald, M. I. Ross, P. F. Mansfield, M. Duvic, S. S. Strom, M. R. Spitz, and Q. Wei DNA Repair Gene XRCC3 241Met Variant Is Not Associated with Risk of Cutaneous Malignant Melanoma Cancer Epidemiol. Biomarkers Prev., October 1, 2002; 11(10): 1142 - 1143. [Full Text] [PDF]
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E. J. Duell, E. A. Holly, P. M. Bracci, J. K. Wiencke, and K. T. Kelsey A Population-based Study of the Arg399Gln Polymorphism in X-Ray Repair Cross- Complementing Group 1 (XRCC1) and Risk of Pancreatic Adenocarcinoma Cancer Res., August 15, 2002; 62(16): 4630 - 4636. [Abstract] [Full Text] [PDF]
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J. Tuimala, G. Szekely, S. Gundy, A. Hirvonen, and H. Norppa Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity Carcinogenesis, June 1, 2002; 23(6): 1003 - 1008. [Abstract] [Full Text] [PDF]
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 R. M. Taylor, A. Thistlethwaite, and K. W. Caldecott Central Role for the XRCC1 BRCT I Domain in Mammalian DNA Single-Strand Break Repair Mol. Cell. Biol., April 15, 2002; 22(8): 2556 - 2563. [Abstract] [Full Text] [PDF]
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S.-M. Hou, S. Falt, S. Angelini, K. Yang, F. Nyberg, B. Lambert, and K. Hemminki The XPD variant alleles are associated with increased aromatic DNA adduct level and lung cancer risk Carcinogenesis, April 1, 2002; 23(4): 599 - 603. [Abstract] [Full Text] [PDF]
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