Department of Genetics, University of Leicester, Department of Cancer Studies and Molecular Medicine, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester, United Kingdom.
Int J Radiat Oncol Biol Phys. 2012 Nov 15;84(4):1031-6. doi: 10.1016/j.ijrobp.2012.02.018. Epub 2012 Jun 6.
In patients receiving radiotherapy for breast cancer where the heart is within the radiation field, cutaneous telangiectasiae could be a marker of potential radiation-induced heart disease. We hypothesized that single nucleotide polymorphisms (SNPs) in genes known to cause heritable telangiectasia-associated disorders could predispose to such late, normal tissue vascular damage.
The relationship between cutaneous telangiectasia as a late normal tissue radiation injury phenotype in 633 breast cancer patients treated with radiotherapy was examined. Patients were clinically assessed for the presence of cutaneous telangiectasia and genotyped at nine SNPs in three candidate genes. Candidate SNPs were within the endoglin (ENG) and activin A receptor, type II-like 1 (ACVRL1) genes, mutations in which cause hereditary hemorrhagic telangiectasia and the ataxia-telangiectasia mutated (ATM) gene associated with ataxia-telangiectasia.
A total of 121 (19.1%) patients exhibited a degree of cutaneous telangiectasiae on clinical examination. Regression was used to examine the associations between the presence of telangiectasiae in patients who underwent breast-conserving surgery, controlling for the effects of boost and known brassiere size (n=388), and individual geno- or haplotypes. Inheritance of ACVRL1 SNPs marginally contributed to the risk of cutaneous telangiectasiae. Haplotypic analysis revealed a stronger association between inheritance of a ATM haplotype and the presence of cutaneous telangiectasiae, fibrosis and overall toxicity. No significant association was observed between telangiectasiae and the coinheritance of the candidate ENG SNPs.
Genetic variation in the ATM gene influences reaction to radiotherapy through both vascular damage and increased fibrosis. The predisposing variation in the ATM gene will need to be better defined to optimize it as a predictive marker for assessing radiotherapy late effects.
在接受乳腺癌放射治疗的患者中，如果心脏位于放射野内，皮肤毛细血管扩张症可能是潜在放射诱导性心脏病的标志物。我们假设，已知导致遗传性毛细血管扩张症相关疾病的基因中的单核苷酸多态性（SNP）可能使这种晚期正常组织血管损伤易于发生。
研究了 633 例接受放射治疗的乳腺癌患者中晚期正常组织放射损伤表型皮肤毛细血管扩张症与放射治疗的关系。通过临床评估患者皮肤毛细血管扩张症的存在情况，并对三个候选基因中的 9 个 SNP 进行基因分型。候选 SNP 位于内皮糖蛋白（ENG）和激活素 A 受体，II 型样 1（ACVRL1）基因内，这些基因突变导致遗传性出血性毛细血管扩张症和与共济失调毛细血管扩张症突变（ATM）基因相关的共济失调毛细血管扩张症。
共有 121 例（19.1%）患者在临床检查中出现一定程度的皮肤毛细血管扩张症。回归用于检查在接受保乳手术的患者中，控制了升压和已知胸罩尺寸（n=388）的影响以及个体基因型或单倍型之间的毛细血管扩张症的存在之间的关联。ACVRL1 SNP 的遗传轻度增加了皮肤毛细血管扩张症的风险。单倍型分析显示，ATM 单倍型的遗传与皮肤毛细血管扩张症、纤维化和整体毒性的存在之间存在更强的关联。未观察到毛细血管扩张症与候选 ENG SNP 的共同遗传之间存在显著相关性。
ATM 基因中的遗传变异通过血管损伤和纤维化增加影响放射治疗反应。需要更好地定义 ATM 基因中易感性变异，以将其优化为评估放射治疗晚期效应的预测标志物。
