ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy
ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy
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DOI：
10.1016/j.ijrobp.2005.09.014
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发表时间：
2006-03-01
影响因子：
7
通讯作者：
Rosenstein, BS
中科院分区：
文献类型：
--
作者：
Andreassen, CN;Overgaard, J;Rosenstein, BS
目的：为了检验这一假设，即与不具有该基因中的DNA序列变异的患者相比，ATM基因中的遗传变异携带者的女性在用于治疗乳腺癌的放疗后更可能发展皮下纤维化。从41名接受乳腺癌切除术后放射治疗的妇女建立的成纤维细胞系中分离的DNA样本筛选遗传变异在ATM中使用变性高效液相色谱法（DHPLC）。最少随访2年，使分析的晚期效应，产生剂量-反应曲线，并估计剂量，导致50%的发病率3级纤维化（ED 50）。结果：共26个遗传变异的ATM基因的表达部分，或在10个碱基内的每个外显子的区域，包括假定的剪接位点，在22例患者中检测到。对于无序列变异的患者计算的ED 50（95%置信区间）为60.2（55.7-65.1）戈伊，与具有任何ATM序列异常的患者组的ED 50（58.4（54.0-63.1）Gy戈伊）无显著差异。ED 50为53.7（50.2-57.5）戈伊，对于那些在核苷酸5557处的G-->A多态性纯合或杂合的患者，其导致ATM蛋白的位置1853处的天冬酰胺取代天冬氨酸，显著低于非该序列变异携带者的ED 50 60.8（57.0-64.8）戈伊。这导致增强比（ED 50值之比）为1.13（1.05-1.22），显着大于1。结论：本研究结果表明ATM密码子1853 Asn/Asp和Asn/Asn基因型之间存在相关性。接受放射治疗的乳腺癌患者发生3级纤维化。(C)2006年爱思唯尔公司
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 (ED50).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 ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->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 ED50 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 ED50 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. (C) 2006 Elsevier Inc.