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Polymorphisms in the DNA Repair Enzyme XPD are Associated with Increased Levels of PAH–DNA Adducts in a Case-Control Study of Breast Cancer

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Abstract

We present findings on the associations between DNA adduct levels in breast tissue, risk of breast cancer, and polymorphisms in the DNA repair enzyme XPD. Breast cancer cases, benign breast disease (BBD) controls, and healthy controls were enrolled. Polycyclic aromatic hydrocarbons (PAH)–DNA adduct levels were measured by immunohistochemistry in breast tissue samples from cases and BBD controls. XPD polymorphisms at codons 312 and 751 was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis using white blood cell DNA. Neither of the polymorphisms were associated with case-control status, both in comparisons of cases and BBD controls, and cases and healthy controls. XPD polymorphisms at codons 312 and 751 were associated with higher levels of PAH–DNA in tumor tissue from breast cancer cases. Subjects with an Asp/Asn or Asn/Asn polymorphic genotype in codon 312 of XPD had elevated levels of PAH–DNA adducts compared to subjects with the Asp/Asp genotype (0.55 optical density (OD) v.s. 0.33 OD, p < 0.01). PAH–DNA adducts were associated with increasing copy number of the Gln allele for the codon 751 polymorphism (p for trend <0.01). Among subjects with the Asp/Asn or Asn/Asn genotype at codon 312, adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.55 OD v.s. 0.36 OD, p = 0.003). Among subjects with the Gln/Gln genotype at codon 751 adduct levels were higher in tumor tissue compared to tissue from BBD controls (0.68 OD v.s. 0.40 OD, p = 0.01). The trend of increasing PAH–DNA adduct levels with either the Asn/Asn or Gln/Gln genotype was greater in tumor tissue than the trend in BBD control tissue.

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References

  1. Cancer Facts and Figures. American Cancer Society, 2001

  2. Rockhill B, Weinberg CR, Newman B: Population attributable fraction estimation for established breast cancer risk factors: considering the issues of high prevalence and unmodifiability. Am J Epidemiol 147(9): 826–833, 1998

    PubMed  Google Scholar 

  3. Madigan M, Ziegler R, Benichou J, Byrne C, Hoover R: Pro-portion of breast cancer cases in the United States explained by well-established risk factors. J Natl Cancer Inst 87(22): 1681–1685, 1995

    PubMed  Google Scholar 

  4. Rundle A, Tang D, Hibshoosh H, Estabrook A, Schnabel F, Cao W, Grumet S, Perera FP: The relationship between ge-netic damage from polycyclic aromatic hydrocarbons in breast tissue and breast cancer. Carcinogenesis 21(7): 1281–1289, 2000

    PubMed  Google Scholar 

  5. El-Bayoumy K: Environmental carcinogens that may be involved in human breast cancer etiology. Chem Res Toxicol 5: 585–590, 1992

    PubMed  Google Scholar 

  6. Perera FP, Estabrook A, Hewer A, Channing KM, Rundle A, Mooney LA, Whyatt R, Phillips DH: Carcinogen-DNA ad-ducts in human breast tissue. Cancer Epi Biomark Prev 4: 233–238, 1995

    Google Scholar 

  7. Li D, Zhang W, Sahin AA, Hittelman WN: DNA adducts in normal tissue adjacent to breast cancer: a review. Cancer Detect Prevent 23(6): 454–462, 1999

    PubMed  Google Scholar 

  8. Rundle A, Tang D, Zhou J, Cho S, Perera FP: The association between glutathione S-transferase M1 genotype and poly-cyclic aromatic hydrocarbon-DNA adducts in breast tissue. Cancer Epi Biomark Prev 10: 1079–1085, 2000

    Google Scholar 

  9. Polynuclear aromatic compounds. Part 1. Chemical, environmental and experimental data. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Vol. 32, International Agency for Research on Cancer, Lyon, France, 1983, pp 1–453 10.

  10. Peltonen KDA: Polycyclic aromatic hydrocarbons: chem-istry of DNA adduct formation. J Occup Environ Med 37(1): 52–58, 1995

    PubMed  Google Scholar 

  11. EPA. Toxicological Profile for B(a)P. Oak Ridge National Laboratory, Oak Ridge, TN, 1990

    Google Scholar 

  12. Moore CJ, Tricomi WA, Gould MN: Interspecies comparison of polycyclic aromatic hydrocarbon metabolism in human and rat mammary epithelial cells. Cancer Res 46: 4946–4952, 1986

    PubMed  Google Scholar 

  13. Calaf G, Russo J: Transformation of human breast epithelial cells by chemical carcinogens. Carcinogenesis 14: 483–492, 1993

    PubMed  Google Scholar 

  14. Eldridge SR, Gould MN, Butterworth BE: Genotoxicity of environmental agents in human mammary epithelial cells. Cancer Res 52: 5617–5621, 1992

    PubMed  Google Scholar 

  15. Mane SS, Purnell DM, Hsu I-C: Genotoxic effects of five polycyclic aromatic hydrocarbons in human and rat mammary epithelial cells. Environ Molec Mutagen 15: 78–82, 1990

    Google Scholar 

  16. Miller EC, Miller JA: Mechanisms of chemical carcinogene-sis. Cancer 47: 1055–1064, 1981

    Google Scholar 

  17. Tang D, Chiamprasert S, Santella RM, Perera FP: Molecular epidemiology of lung cancer: carcinogen-DNA adducts, GSTM1 and risk. Proc AACR 284, 1995

  18. Tang D, Rundle A, Warburton D, Santella RM, Tsai WY, Chiamprasert S, Hsu YZ, Perera FP: Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers. Carcinogenesis 19(11): 1949–1953, 1998

    PubMed  Google Scholar 

  19. Helzlsouer KJ, Harris EL, Parshad R, Fogel S, Bigbee WL, Sanford KK: Familial clustering of breast cancer: possible interaction between DNA repair proficiency and radiation ex-posure in the development of breast cancer. Intl J Cancer 64(1): 14–17, 1995

    Google Scholar 

  20. Wei Q, Spitz MR: The role of DNA repair capacity in susceptibility to lung cancer: a review. Cancer Metastasis Rev 16(3–4): 295–307, 1997

    PubMed  Google Scholar 

  21. Mohrenweiser H, Jones I: Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation? Mutat Res 400(1–2): 15–24, 1998

    PubMed  Google Scholar 

  22. Robles AI, Wang XW, Harris CC: Drug-induced apoptosis is delayed and reduced in XPD lymphoblastoid cell lines: possible role of TFIIH in p53-mediated apoptotic cell death. Oncogene 18(33): 4681–4688, 1999

    PubMed  Google Scholar 

  23. Wang XW, Vermeulen W, Coursen JD, Gibson M, Lupold SE, Foresster K, Xu G, Elmore L, Yeh H, Hoeijmakers JH, Harris CC: XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. Genes Dev 10(10): 1219–1232, 1996

    PubMed  Google Scholar 

  24. Miller MC, Mohrenweiser HW, Bell DA: Genetic variabil-ity in susceptibility and response to toxicants. Toxicol Lett 120(1–3): 269–280, 2001

    PubMed  Google Scholar 

  25. Tomescu D, Kavanagh G, Ha T, Campbell H, Melton DW: Nucleotide excision repair gene XPD polymorphisms and genetic predisposition to melanoma. Carcinogenesis 22(3): 403–408, 2001

    PubMed  Google Scholar 

  26. Lunn RM, Helzlsouer KJ, Parshad R, Umbach DM, Harris EL, Sanford KK, Bell DA: XPD polymorphisms: effects on DNA repair proficiency. Carcinogenesis 21(4): 551–555, 2000

    PubMed  Google Scholar 

  27. Sturgis EM, Zheng R, Li L, Castillo EJ, Eicher SA, Chen M, Strom SS, Spitz MR, Wei Q: XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis. Carcinogenesis 21(12): 2219–2223, 2000

    PubMed  Google Scholar 

  28. Lehmann AR: The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases. Genes Dev 15: 15–23, 2001.

    PubMed  Google Scholar 

  29. Thompson LH, West MG: XRCC1 keeps DNA from getting stranded. Mutat Res 459: 1–18, 2000

    PubMed  Google Scholar 

  30. Braithwaite E, Wu X, Wang Z: Repair of DNA lesions induced by polycyclic aromatic hydrocarbons in human cell-free ex-tracts: involvement of two excision repair mechanisms in vitro. Carcinogenesis 19(7): 1239–1246, 1998

    PubMed  Google Scholar 

  31. Hyytinen ER, Frierson HF, Sipe TW, Li CL, Degeorges A, Sikes RA, Chung LW, Dong JT: Loss of heterozygosity and lack of mutations of the XPG/ERCC5 DNA repair gene at 13q33 in prostate cancer. Prostate 41(3): 190–195, 1999

    PubMed  Google Scholar 

  32. Hoeijmakers JH, Egly JM, Vermeulen W: TFIIH: a key component in multiple DNA transactions. Curr Opinion Genetics Dev 6(1): 26–33, 1996

    Google Scholar 

  33. Drapkin R, Reardon JT, Ansari A, Huang JC, Zawel L, Ahn K, Sancar A, Reinberg D: Dual role of TFIIH in DNA excision repair and in transcription by RNA polymerase II. Nature 368(6473): 769–772, 1994

    PubMed  Google Scholar 

  34. Seroz T, Perez C, Bergmann E, Bradsher J, Egly JM: p44/SSL1, the regulatory subunit of the XPD/RAD3 helicase, plays a crucial role in the transcriptional activity of TFIIH. J Biol Chem 275(43): 33260–33266, 2000

    PubMed  Google Scholar 

  35. Winkler GS, Araujo SJ, Fiedler U, Vermeulen W, Coin F, Egly JM, Hoeijmakers JH, Wood RD, Timmers HT, Weeda G: TFIIH with inactive XPD helicase functions in transcription initiation but is defective in DNA repair. J Biol Chem 275(6): 4258–4266, 2000

    PubMed  Google Scholar 

  36. Spitz MR, Wu X, Wang Y, Wang LE, Shete S, Amos CI, Guo Z, Lei L, Mohrenweiser H, Wei Q: Modulation of nucle-otide excision repair capacity by XPD polymorphisms in lung cancer patients. Cancer Res 61(4): 1354–1357, 2001

    PubMed  Google Scholar 

  37. Moustacchi E: DNA damage and repair: consequences on dose-responses. Mutat Res 464: 35–40, 2000

    PubMed  Google Scholar 

  38. Vogel U, Hedayati M, Dybdahl M, Grossman L, Nexo BA: Polymorphisms of the DNA repair gene XPD: correlations with risk of basal cell carcinoma revisited. Carcinogenesis 22(6): 899–904, 2001

    PubMed  Google Scholar 

  39. David-Beabes GL, Lunn RM, London SJ: No association between the XPD (Lys751G1n) polymorphism or the XRCC3 (Thr241Met) polymorphism and lung cancer risk. Cancer Epi Biomark Prev 10(8): 911–912, 2001

    Google Scholar 

  40. Zhang Y, Weksler B, Wang L, Schwartz J, Santella R:Immunohistochemical detection of polycyclic aromatic hydrocarbon-DNA damage in human blood vessels of smokers and non-smokers. Atherosclerosis 140(2): 325–331, 1998

    PubMed  Google Scholar 

  41. Rundle A, Tang D, Hibshoosh H, Schnabel F, Kelly A, Levine R, Zhou J, Link B, Perera FP: Molecular epidemiologic studies of polycyclic aromatic hydrocarbon-DNA adducts and breast cancer. Environ Molec Mutagen 39(2–3): 201–207, 2002

    Google Scholar 

  42. Shrout PE, Fleiss J: Intra-class correlations: uses in assessing rater reliability. Psyc Bull 86(2): 420–428, 1979

    Google Scholar 

  43. Flanders WD, DerSimonian R, Freedman DS: Interpretation of linear regression models that include transformations or interaction terms. Ann Epi 2(5): 735–744, 1992

    Google Scholar 

  44. Helzlsouer KJ, Harris EL, Parshad R, Perry HR, Price FM, Sanford KK: DNA repair proficiency: potential susceptibility factor for breast cancer. J Natl Cancer Inst 88(11): 754–755, 1996

    PubMed  Google Scholar 

  45. Butkiewicz D, Rusin M, Enewold L, Shields PG, Chorazy M, Harris CC: Genetic polymorphisms in DNA repair genes and risk of lung cancer. Carcinogenesis 22(4): 593–597, 2001

    PubMed  Google Scholar 

  46. Dybdahl M, Vogel U, Frentz G, Wallin H, Nexo BA: Polymorphisms in the DNA repair gene XPD: correlations with risk and age at onset of basal cell carcinoma. Cancer Epi Biomark Prev 8: 77–81, 1999

    Google Scholar 

  47. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, Krogh V, Munnia A, Tumino R, Polidoro S, Piazza A, Vineis P: XRCC1, XRCC3, XPD gene polymor-phisms, smoking and 32 P-DNA adducts in a sample of healthy subjects. Carcinogenesis 22: 1437–1445, 2001

    PubMed  Google Scholar 

  48. Palli D, Russo A, Masala G, Saieva C, Guarrera S, Carturan S, Munnia A, Matullo G, Peluso M: DNA-adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample. Intl J Cancer 94: 121–127, 2001

    Google Scholar 

  49. Cleaver JE, Karplus K, Kashani-Sabet M, Limoli CL: Nucle-otide excision repair: 'a legacy of creativity'. Mutat Res 485: 23–36, 2001

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Environmental Health Sciences, Columbia-Presbyterian Medical Center, New York, NY, USA

    Deliang Tang, Stan Cho, Senqing Chen, David Phillips, Jingzhi Zhou, Yanzhi Hsu & Frederica P. Perera

  2. Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York, NY, USA

    Andrew Rundle

  3. Department of Pathology, Columbia-Presbyterian Medical Center, New York, NY, USA

    Freya Schnabel

  4. Department of Surgery, Columbia-Presbyterian Medical Center, New York, NY, USA

    Alison Estabrook

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  1. Deliang Tang
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Tang, D., Cho, S., Rundle, A. et al. Polymorphisms in the DNA Repair Enzyme XPD are Associated with Increased Levels of PAH–DNA Adducts in a Case-Control Study of Breast Cancer. Breast Cancer Res Treat 75, 159–166 (2002). https://doi.org/10.1023/A:1019693504183

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