Ho Alice Y, Fan Grace, Atencio David P, Green Sheryl, Formenti Silvia C, Haffty Bruce G, Iyengar Preetha, Bernstein Jonine L, Stock Richard G, Cesaretti Jamie A, Rosenstein Barry S
Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):677-84. doi: 10.1016/j.ijrobp.2007.04.012. Epub 2007 May 22.
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.
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.
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).
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.
ATM基因产物是细胞周期调控和基因组监测的核心组成部分。我们推测，ATM基因的DNA序列改变可预测早期乳腺癌患者接受外照射放疗后的不良反应。
对131例接受保乳手术和辅助放疗且随访至少2年的患者，使用血液淋巴细胞中的DNA筛查ATM基因的序列改变。采用变性高效液相色谱法鉴定基因变异。应用放射治疗肿瘤学组关于皮肤和皮下组织的晚期发病率评分方案来量化辐射诱导的效应。
131例患者中，51例的ATM序列改变位于外显子内或每个外显子侧翼的短内含子区域，这些区域包含假定的剪接位点区域。在这51例患者中，21例（41%）表现出至少2级的晚期放射反应。相比之下，80例无ATM序列变异的患者中，只有18例（23%）有辐射诱导的不良反应，优势比为2.4（95%置信区间，1.1 - 5.2）。15例患者在核苷酸5557处存在G→A多态性的杂合子，这导致ATM蛋白第1853位的天冬氨酸被天冬酰胺取代。在这15例患者中，8例（53%）表现出2 - 4级晚期反应，而116例无此改变的患者中有31例（27%）出现该反应，优势比为3.1（95%置信区间，1.1 - 9.4）。
位于ATM基因的序列变异，尤其是5557 G→A多态性，可能预测乳腺癌患者的晚期辐射不良反应。
