Breast Cancer Research and Treatment

, Volume 101, Issue 1, pp 65–71 | Cite as

Breast Cancer Risk is not Associated with Polymorphic Forms of Xeroderma Pigmentosum Genes in a Cohort of Women from Washington County, Maryland

  • T. J. Jorgensen
  • K. Visvanathan
  • I. Ruczinski
  • L. Thuita
  • S. Hoffman
  • K. J. Helzlsouer
Epidemiology

Abstract

Background

The genes mutated in the cancer-prone syndrome, xeroderma pigmentosum (XP genes), have been well studied both biochemically and mechanistically. These genes are important components of the DNA nucleotide excision repair (NER) pathway, which protects against environmentally-induced cancers. XP genes are also downstream of the hereditary breast cancer syndrome gene, BRCA1, suggesting that XP genes may be important to hereditary forms of breast cancer as well. Although mutated XP genes are rare, polymorphic forms with potential functional deficiencies are common, and could pose a significant cancer risk in the general population.

Hypothesis

This study tested the hypothesis that common polymorphic variants of XP genes were associated with the risk of breast cancer among a population of women in Washington County, Maryland.

Methods

Five single nucleotide polymorphisms (SNPs) among four XP genes (XPC, XPD, XPF and XPG) were genotyped from DNA samples collected at baseline, and then analyzed by conditional logistic regression for association with the incidence of breast cancer. 321 cases were individually matched to 321 controls, by age and menopausal status.

Results

No significant associations were found between breast cancer risk and any of the XP genotypes. Odds ratios for all genotypes ranged from 0.61 to 1.14, and none were statistically significant. Adjustment and stratification for family history of breast cancer did not alter the findings.

Conclusion

These results suggest that polymorphisms of XP genes are not likely to be significant risk factors for women within the general population. This study did not address, however, risks for subpopulations of women with high exposures to DNA damaging agents.

Keywords

Breast cancer DNA repair Xeroderma pigmentosum Single nucleotide polymorphisms (SNPs) Genetic cancer risk 

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Notes

Acknowledgements

Grant Support: Research was funded by a National Cancer Institute Breast Spore Award (P50 CA88843), and the National Institute of Aging 5U01AG018033. T.J.J. was funded by an NIH Ruth L. Kirschstein Senior Fellow Award (NCI F33 CA09817-01). K.V. is a recipient an ASCO Career Development Award and an NIH Preventive Oncology Academic Award (NCI K07 CA111948). I.R. was supported, in part, by the Maryland Cigarette Restitution Fund Research Grant to the Johns Hopkins Medical Institutions and NIH grant CA 074841.

References

  1. 1.
    Lindahl T, Wood RD (1999) Quality control by DNA repair. Science 286:1897–1905PubMedCrossRefGoogle Scholar
  2. 2.
    Kraemer KH, Levy DD, Parris CN, Gozukara EM, Moriwaki S, Adelberg S, Seidman MM (1994) Xeroderma pigmentosum and related disorders: examining the linkage between defective DNA repair and cancer. J Invest Dermatol 103 Suppl. 5:96S–101SGoogle Scholar
  3. 3.
    Kraemer KH, Lee M-M, Andrews AD, Lambert WC (1994) The role of sunlight and DNA repair in melanoma and nonmelanoma skin cancer: The xeroderma pigmentosum paradigm. Arch Dermatol 130:1018–1021PubMedCrossRefGoogle Scholar
  4. 4.
    Somasundaram K (2003) Breast cancer gene 1 (BRCA1): role in cell cycle regulation and DNA repair—perhaps through transcription. J Cell Biochem 88(6):1084–1091PubMedCrossRefGoogle Scholar
  5. 5.
    El-Deiry WS (2002) Transactivation of repair genes by BRCA1. Cancer Biol Ther 1(5):490–491PubMedGoogle Scholar
  6. 6.
    Reardon JT, Sancar A (2005) Nucleotide excision repair. Prog Nucleic Acid Res Mol Biol 79:183–235PubMedGoogle Scholar
  7. 7.
    Helzlsouer KJ, Alberg AJ, Huang HY, Hoffman SC, Strickland PT, Brock JW, Burse VW, Needham LL, Bell DA, Lavigne JA, etal (1999) Serum concentrations of organochlorine compounds and the subsequent development of breast cancer. Cancer Epidemiol Biomarkers Prev 8(6):525–532Google Scholar
  8. 8.
    Klintschar M, Neuhuber F (2000) Evaluation of an alkaline lysis method for the extraction of DNA from whole blood and forensic stains for STR analysis. J Forensic Sci 45(3):669–673PubMedGoogle Scholar
  9. 9.
    Rubin DB (1996) Multiple imputation after 18+ years. J Am Stat Assoc 91(434):473–489CrossRefGoogle Scholar
  10. 10.
    Schafer JL (1997) Analysis of incomplete multivariate data. vol. 72. Chapman & Hall, New YorkGoogle Scholar
  11. 11.
    Greenland S, Finkle WD (1995) A critical look at methods for handling missing covariates in epidemiologic regression analyses. Am J Epidemiol 142(12):1255–1264PubMedGoogle Scholar
  12. 12.
    Brewster AM, Jorgensen TJ, Ruczinski I, Huang HY, Hoffman S, Thuita L, Newschaffer C, Lunn RM, Bell D, Helzlsouer KJ (2006) Polymorphisms of the DNA repair genes XPD (Lys751Gln) and XRCC1 (Arg399Gln and Arg194Trp): relationship to breast cancer risk and familial predisposition to breast cancer. Breast Cancer Res Treat 95(1):73–80PubMedCrossRefGoogle Scholar
  13. 13.
    Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4(11):850–860PubMedCrossRefGoogle Scholar
  14. 14.
    Lehmann AR (2003) DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. Biochimie 85(11):1101–1111PubMedCrossRefGoogle Scholar
  15. 15.
    Amiel A, Peretz G, Slor H, Weinstein G, Fejgin MD (2004) Molecular cytogenetic parameters in fibroblasts from patients and carriers of xeroderma pigmentosum. Cancer Genet Cytogenet 149(2):154–160PubMedCrossRefGoogle Scholar
  16. 16.
    Cheo DL, Meira LB, Burns DK, Reis AM, Issac T, Friedberg EC (2000) Ultraviolet B radiation-induced skin cancer in mice defective in the Xpc, Trp53, and Apex (HAP1) genes: genotype-specific effects on cancer predisposition and pathology of tumors. Cancer Res 60(6):1580–1584PubMedGoogle Scholar
  17. 17.
    Antoniou AC, Pharoah PD, McMullan G, Day NE, Ponder BA, Easton D (2001) Evidence for further breast cancer susceptibility genes in addition to BRCA1 and BRCA2 in a population-based study. Genet Epidemiol 21(1):1–18PubMedCrossRefGoogle Scholar
  18. 18.
    Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, Peto J, Ponder BJ, Easton DF (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86(1):76–83PubMedCrossRefGoogle Scholar
  19. 19.
    Goode EL, Ulrich CM, Potter JD (2002) Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev 11(12):1513–1530PubMedGoogle Scholar
  20. 20.
    Zhang L, Zhang Z, Yan W (2005) Single nucleotide polymorphisms for DNA repair genes in breast cancer patients. Clin Chim Acta 359(1–2):150–155PubMedCrossRefGoogle Scholar
  21. 21.
    Spillare EA, Wang XW, von Kobbe C, Bohr VA, Hickson ID, Harris CC (2005) Redundancy of DNA helicases in p53-mediated apoptosis. Oncogene 25(14):2119–2123CrossRefGoogle Scholar
  22. 22.
    Seker H, Butkiewicz D, Bowman ED, Rusin M, Hedayati M, Grossman L, Harris CC (2001) Functional significance of XPD polymorphic variants: attenuated apoptosis in human lymphoblastoid cells with the XPD 312 Asp/Asp genotype. Cancer Res 61(20):7430–7434PubMedGoogle Scholar
  23. 23.
    Rothkamm K, Lobrich M (2003) Evidence for a lack of DNA double-strand break repair in human cells exposed to␣very low X-ray doses. Proc Natl Acad Sci USA 100(9):5057–5062PubMedCrossRefGoogle Scholar
  24. 24.
    Terry MB, Gammon MD, Zhang FF, Eng SM, Sagiv SK, Paykin AB, Wang Q, Hayes S, Teitelbaum SL, Neugut AI, etal (2004) Polymorphism in the DNA repair gene XPD, polycyclic aromatic hydrocarbon-DNA adducts, cigarette smoking, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 13(12):2053–2058PubMedGoogle Scholar
  25. 25.
    Smith TR, Levine EA, Perrier ND, Miller MS, Freimanis RI, Lohman K, Case LD, Xu J, Mohrenweiser HW, Hu JJ (2003) DNA-repair genetic polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 12(11 Pt 1):1200–1204PubMedGoogle Scholar
  26. 26.
    Kumar R, Hoglund L, Zhao C, Forsti A, Snellman E, Hemminki K (2003) Single nucleotide polymorphisms in the XPG gene: determination of role in DNA repair and breast cancer risk. Int J Cancer 103(5):671–675PubMedCrossRefGoogle Scholar
  27. 27.
    Forsti A, Angelini S, Festa F, Sanyal S, Zhang Z, Grzybowska E, Pamula J, Pekala W, Zientek H, Hemminki K, etal (2004) Single nucleotide polymorphisms in breast cancer. Oncol Rep 11(4):917–922PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • T. J. Jorgensen
    • 1
  • K. Visvanathan
    • 2
  • I. Ruczinski
    • 3
  • L. Thuita
    • 2
  • S. Hoffman
    • 2
    • 4
  • K. J. Helzlsouer
    • 2
    • 4
    • 5
  1. 1.Department of Radiation Medicine, Lombardi Comprehensive Cancer CenterGeorgetown UniversityWashingtonUSA
  2. 2.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Department of BiostatisticsJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  4. 4.George W. Comstock Center for Public Health Research and PreventionHagerstownUSA
  5. 5.The Prevention and Research Center, Mercy Medical CenterBaltimoreUSA

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