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Carcinogenesis Advance Access published online on June 15, 2006
Carcinogenesis, doi:10.1093/carcin/bgl103
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© The Author 2006. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received February 7, 2006
Revised May 11, 2006
Accepted May 27, 2006

CARCINOGENESIS

Radiation clastogenesis and cell cycle checkpoint function as functional markers of breast cancer risk

William K. Kaufmann 1 *, Leonid Filatov 1 *, Stephen E. Oglesbee 1, Dennis A. Simpson 1, Marc A. Lotano 1, Hayley D. McKeen 1, Lynda R. Sawyer 1, Dominic T. Moore 1, Robert C. Millikan 1, Marila Cordeiro-Stone 1, and Lisa A. Carey 1

1 Lineberger Comprehensive Cancer Center, Center for Environmental Health and Susceptibility, Departments of Pathology and Laboratory Medicine, Biostatistics, Epidemiology, and Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295

* To whom correspondence should be addressed.
William K. Kaufmann, E-mail: wkarlk{at}med.unc.edu


  Abstract

Background: Familial breast cancer is associated with mutations in several genes (BRCA1, BRCA2, p53, ATM) whose protein products protect against radiation-induced genotoxicity. This study tested whether sporadic breast cancer was associated with constitutive radiation hypersensitivity. Methods: Blood lymphocytes and EBV-transformed lymphoblasts from patients with newly diagnosed breast cancer and controls without cancer were evaluated for ionizing radiation (IR)-induced chromosomal aberrations and cell cycle delays. Lymphoblasts from patients with ataxia telangiectasia (AT) and heterozygous AT carriers were tested as positive controls for radiation hypersensitivity. Results: Lymphoblasts from AT patients and AT carriers displayed G2-irradiation, chromosomal hypersensitivity (GICH). Irradiated G2 phase lymphocytes from breast cancer cases and controls displayed 3-fold inter-individual variation in frequencies of chromatid damage. However, the percentage of breast cancer cases with damage frequencies in excess of two standard deviations of the control mean (8/102 or 8%) was not significantly elevated compared to controls (2/48 or 4%, p=0.5). Lymphoblasts sampled 24 h after 3 Gy of IR also varied in the ratio's of cells with 4N and 2N DNA content (4N/2N ratio), as a measure of cell cycle checkpoint function. 4N/2N ratio's in irradiated lymphoblasts were strongly correlated with the fractions of S phase cells in un-irradiated control cultures (Pearson's correlation coefficient, r = 0.87). After normalization to S fraction, the radiation-induced increment in the 4N/2N ratio was significantly elevated in AT lymphoblasts but not in lymphoblasts from AT carriers. The fraction of breast cancer cases with reduced checkpoint function (2/45 or 4%) was equal to the control fraction (2/45 or 4%). For breast cancer cases and controls, GICH in primary lymphocytes was not associated with reduced cell cycle checkpoint function in lymphoblasts. Conclusion: Constitutive radiation hypersensitivity in blood lymphocytes and lymphoblasts was not a useful biomarker for identifying women at increased risk of breast cancer.

*deceased
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