Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy
Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy
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DOI：
10.1016/j.ijrobp.2007.04.012
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发表时间：
2007-11-01
影响因子：
7
通讯作者：
Rosenstein, Barry S.
中科院分区：
文献类型：
--
作者：
Ho, Alice Y.;Fan, Grace;Rosenstein, Barry S.
目的：ATM基因产物是细胞周期调控和基因组监测的中心成分。我们假设ATM中的DNA序列改变可以预测早期乳腺癌外照射治疗后的不良反应。方法和材料：共131例接受保乳手术和辅助放射治疗的患者接受了保乳手术和辅助放射治疗，对ATM中的DNA序列改变进行了筛查。用变性高效液相色谱鉴定基因变异。结果：在131例患者中，51例ATM序列改变位于外显子内或位于每个外显子两侧的短内含子区域，这些内含子包含假定的剪接部位区域。在这51名患者中，21名(41%)表现出最低程度的2级晚期放射反应。相比之下，在80名没有ATM序列变异的患者中，只有18名(23%)出现了辐射诱导的不良反应，优势比为2.4(95%可信区间，1.1-5.2)。15名患者在核苷酸5557处发生G>；A多态杂合，导致ATM蛋白1853位天冬氨酸被天冬氨酸取代。在这15名患者中，8名(53%)表现出2-4级的晚期反应，而在116名没有这种改变的患者中，31名(27%)表现出2-4级的晚期反应，优势比为3.1(95%可信区间，1.1-9.4)。结论：ATM基因上的序列变异，特别是5557G>；A多态，可能预测乳腺癌患者的晚期放射不良反应。(C)2007年爱思唯尔公司。
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. (C) 2007 Elsevier Inc.