ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus (Denmark)
- Department of Oncology, Aarhus University Hospital, Aarhus (Denmark)
- Department of Radiation Oncology, University of Heidelberg, Mannheim Medical Center, Mannheim (Germany)
- Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY (United States)
- Department of Radiation Oncology, New York University School of Medicine, New York, NY (United States)
- Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY (United States) and Department of Radiation Oncology, New York University School of Medicine, New York, NY (United States) and Department of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, NY (United States) and Department of Dermatology, Mount Sinai School of Medicine, New York, NY (United States)
Purpose: To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene. Methods and Materials: DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED{sub 5}). Results: A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED{sub 5} (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED{sub 5} of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED{sub 5} of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G{sup {yields}}A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED{sub 5} of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED{sub 5} values) of 1.13 (1.05-1.22), which was significantly greater than unity. Conclusion: The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy.
- OSTI ID:
- 20793345
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics, Vol. 64, Issue 3; Other Information: DOI: 10.1016/j.ijrobp.2005.09.014; PII: S0360-3016(05)02605-2; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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