Abstract
Risk assessment is now recognized as a multidisciplinary process, extending beyond the scope of traditional epidemiologic methodology to include biological evaluation of interindividual differences in carcinogenic susceptibility. Modulation of environmental exposures by host genetic factors may explain much of the observed interindividual variation in susceptibility to carcinogenesis. These genetic factors include, but are not limited to, carcinogen metabolism and DNA repair capacity. This chapter describes a standardized method for the functional assessment of mutagen sensitivity. This in vitro assay measures the frequency of mutagen-induced breaks in the chromosomes of peripheral blood lymphocytes. Mutagen sensitivity assessed by this method has been shown to be a significant risk factor for tobacco-related maladies, especially those of the upper aerodigestive tract. Mutagen sensitivity may therefore be a useful member of a panel of susceptibility markers for defining high-risk subgroups for chemoprevention trials. This chapter describes methods for and discusses results from studies of mutagen sensitivity as measured by quantifying chromatid breaks induced by clastogenic agents, such as the γ-radiation mimetic DNA cross-linking agent bleomycin and chemicals that form so-called bulky DNA adducts, such as 4-nitroquinoline and the tobacco smoke constituent benzo[a]pyrene, in short-term cultured peripheral blood lymphocytes.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Hsu TC (1983) Genetic instability in the human population: a working hypothesis. Hereditas 98:1–9
Hsu TC, Johnston DA, Cherry LM et al (1989) Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis. Int J Cancer 43: 403–409
Hsu TC, Spitz MR, Schantz SP (1991) Mutagen sensitivity: a biologic marker of cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1:83–89
Wu X, Gu J, Spitz MR (2007) Mutagen sensitivity: a genetic predisposition factor for cancer. Cancer Res 67:3493–3495
Spitz MR, Fueger JJ, Beddingfield NA et al (1989) Chromosome sensitivity to bleomycin-induced mutagenesis, an independent risk factor for upper aerodigestive tract cancers. Cancer Res 49:4626–4628
Schantz SP, Hsu TC, Ainslie N, Moser RP (1989) Young adults with head and neck cancer express increased susceptibility to mutagen-induced chromosome damage. JAMA 262: 3313–3315
Spitz MR, Fueger JJ, Halabi S, Schantz SP, Sample D, Hsu TC (1993) Mutagen sensitivity in upper aerodigestive tract cancer: a case–control analysis. Cancer Epidemiol Biomarkers Prev 2:329–333
Cloos J, Steen I, Joenje H et al (1993) Association between bleomycin genotoxicity and non-constitutional risk factors for head and neck cancer. Cancer Lett 74:161–165
Cloos J, Spitz MR, Schantz SP et al (1996) Genetic susceptibility to head and neck squamous cell carcinoma. J Natl Cancer Inst 88: 530–535
Wu X, Gu J, Hong WK et al (1998) Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract. J Natl Cancer Inst 90:1393–1399
Spitz MR, Hsu TC, Wu XF, Fueger JJ, Amos CI, Roth JA (1995) Mutagen sensitivity as a biologic marker of lung cancer risk in African Americans. Cancer Epidemiol Biomarkers Prev 4:99–103
Strom SS, Wu X, Sigurdson AJ et al (1995) Lung cancer, smoking patterns, and mutagen sensitivity in Mexican-Americans. J Natl Cancer Inst 18:29–33
Wu X, Delclos GL, Annegers FJ et al (1995) A case–control study of wood-dust exposure, mutagen sensitivity, and lung-cancer risk. Cancer Epidemiol Biomarkers Prev 4:583–588
Wu X, Gu J, Amos CI, Jiang H, Hong WK, Spitz MR (1998) A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung cancer cases and controls. Cancer 83:1118–1127
Wu X, Gu J, Patt Y et al (1998) Mutagen sensitivity as a susceptibility marker for human hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 7:567–570
Spitz MR, Lippman SM, Jiang H et al (1998) Mutagen sensitivity as a predictor of tumor recurrence in patients with cancer of the upper aerodigestive tract. J Natl Cancer Inst 90: 243–245
Hsu TC, Feun L, Trizna Z et al (1993) Differential sensitivity among three human subpopulations in response to 4-nitroquinoline- 1-oxide and to bleomycin. Int J Oncol 3: 827–830
Bondy ML, Kyritis AP, Gu J et al (1996) Mutagen sensitivity and risk of glioma: a case–control analysis. Cancer Res 56:1484–1486
Buchholz TA, Wu XF (2001) Radiation-induced chromatid breaks as a predictor of breast cancer risk. Int J Radiat Oncol Biol Phys 49:533–537
Wu X, Hsu TC, Spitz MR (1996) Mutagen sensitivity exhibits a dose–response relationship in case–control studies. Cancer Epidemiol Biomarkers Prev 5:577–578
Wang L-E, Xiong P, Strom SS et al (2005) In vitro sensitivity to ultraviolet B light and skin cancer risk: a case–control analysis. J Natl Cancer Inst 97:1822–1831
Xu YJ, Kim EY, Demple B (1998) Excision of C-4′-oxidized deoxyribose lesions from double-stranded DNA by human apurinic/apyrimidinic endonuclease (Ape1 protein) and DNA polymerase beta. J Biol Chem 273: 28837–28844
Dar ME, Winters TA, Jorgensen TJ (1997) Identification of defective illegitimate recombinational repair of oxidatively-induced DNA double-strand breaks in ataxia-telangiectasia cells. Mutat Res 384:169–179
Thompson LH (1998) Nucleotide excision repair: its relation to human disease. In: Nickoloff JA, Hoekstra MF (eds) DNA Damage and Repair, Volume 2: DNA Repair in Higher Eukaryotes. Humana, Totowa, NJ, pp 335–393
Arce GT, Allen JW, Doerr CL et al (1987) Relationships between benzo(a)pyrene-DNA adducts levels and genotoxic effects in mammalian cells. Cancer Res 47:3388–3395
Wolterbeek AP, Roggeband R, Steenwinkel MJ, Rutten AA, Baan RA (1993) Formation and repair of benzo[a]pyrene-DNA adducts in cultured hamster tracheal epithelium determined by 32P-postlabeling analysis and unscheduled DNA synthesis. Carcinogenesis 14: 463–467
Shou M, Harvey RG, Penning TM (1993) Reactivity of benzo[a]pyrene-7,8-dione with DNA. Evidence for the formation of deoxyguanosine adducts. Carcinogenesis 14:475–482
Tang MS, Pierce JR, Doisy RP, Nazimiec ME, Macleod MC (1992) Differences and similarities in the repair of two benzo[a]pyrene diol epoxide isomers induced DNA adducts by uvrA, uvrB, and uvrC gene products. Biochemistry 31:8429–8436
Xiong P, Bondy ML, Li D et al (2001) Sensitivity to benzo(a)pyrene diol-epoxide associated with risk of breast cancer in young women and modulation by glutathione S-transferase polymorphisms: a case–control study. Cancer Res 61:8465–8469
Kosti O, Byrne C, Meeker KL et al (2010) Mutagen sensitivity, tobacco smoking and breast cancer risk: a case–control study. Carcinogenesis 31:654–659
Jin C, Jin Y, Wennerberg J, Rosenquist B, Mertens F (2008) Increased sensitivity to bleomycin in upper aerodigestive tract mucosa of head and neck squamous cell carcinoma patients. Mutat Res 652:30–37
Chatham Workshop Conference (1971) Chatham workshop conference on karyological monitoring of normal cell populations. International association of biological standardization. Cape Cod, MA
Hsu TC, Wu X, Trizna Z (1996) Mutagen sensitivity in humans: a comparison between two nomenclature systems for recording chromatid breaks. Cancer Genet Cytogenet 87: 127–132
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Humana Press
About this protocol
Cite this protocol
Wu, X., Zheng, YL., Hsu, T.C. (2014). Mutagen Sensitivity as Measured by Induced Chromatid Breakage as a Marker of Cancer Risk. In: Keohavong, P., Grant, S. (eds) Molecular Toxicology Protocols. Methods in Molecular Biology, vol 1105. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-739-6_15
Download citation
DOI: https://doi.org/10.1007/978-1-62703-739-6_15
Published:
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-62703-738-9
Online ISBN: 978-1-62703-739-6
eBook Packages: Springer Protocols