| Abstract: |
Purpose: The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer. Methods and Materials: A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify the radiation-induced effects. Results: Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G→A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4). Conclusion: Sequence variants located in the ATM gene, in particular the 5557 G→A polymorphism, may predict for late adverse radiation responses in breast cancer patients. © 2007 Elsevier Inc. All rights reserved. |
| Keywords: |
adult; controlled study; human tissue; aged; aged, 80 and over; middle aged; major clinical study; exon; dna-binding proteins; exons; mutation, missense; radiotherapy, adjuvant; follow up; cell cycle proteins; breast cancer; genes; amino acid substitution; radiotherapy; morbidity; genetic variability; intron; introns; odds ratio; cancer screening; breast neoplasms; oncology; radiation response; confidence interval; confidence intervals; skin; radiation effects; tumors; protein-serine-threonine kinases; heterozygosity; gene identification; nucleotide sequence; tumor suppressor proteins; radiation injuries; atm protein; surgery; predictor variable; dna flanking region; external beam radiotherapy; high performance liquid chromatography; cell cycle regulation; lymphocyte; african americans; polymorphism, genetic; aspartic acid; mastectomy, segmental; asparagine; dna sequences; genetic polymorphism; dna splicing; tissue reaction; atm gene; subcutaneous tissue; genetic variants; late tissue response
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