Genetic Mechanisms of Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

描述（由申请人提供）：治疗25年后，儿童癌症长期幸存者（LTS）的CV死亡率风险比健康人群增加了8倍以上。随着时间的推移，这种风险逐渐增加，似乎部分与蒽环类药物化疗有关。由于预计到2010年，美国20-45岁的年轻人中有1:570成为儿童癌症幸存者，其中一半将接受蒽环类药物治疗，因此了解这种毒性的机制以预防或治疗它变得至关重要。遗传（自然基因型或诱导变化）可能在每个个体对蒽环类药物毒性的易感性中发挥作用。在蒽环类药物心脏毒性的动物模型中，发现不可逆的线粒体损伤，部分与治疗期间的自由基损伤有关，导致晚期心肌病，但尚未在人类中进行研究。已知引起血色素沉着病的基因突变（HFE突变）也可能导致对毒性的易感性。在这项应用中，目的1将是确定在达纳法伯癌症研究所联盟登记的儿童急性淋巴细胞白血病（ALL）幸存者线粒体DNA （mtDNA）突变的频率。我们还将确定接受心脏保护剂右旋razoxane的儿童与未接受心脏保护剂右旋razoxane的儿童之间的突变率是否存在差异。我们将把突变程度与心功能的其他标志物（超声心动图测量和心脏风险的血清生物标志物）联系起来。目的2将通过超声心动图和血清生物标志物来确定HFE突变是否与更大的长期心脏毒性相关。我们将在DFCI ALL联盟中招募总共200名ALL幸存者，他们被纳入研究91-001、95-001和00-001。只有50%的患者接受了心脏保护剂右拉唑烷。mtDNA和HFE研究将在诊断后4年内进行，同时通过超声心动图评估心功能和分析心脏风险的血清生物标志物（血脂、proBNP、hsCRP、cTnT）。我们将确定：1；如果mtDNA突变与先前的蒽环类药物治疗相关的频率较高，并且右唑嗪对这些突变具有保护作用2。如果mtDNA突变与心肌病、过早动脉粥样硬化的心血管风险增加有关；3. 如果HFE突变与蒽环类药物的心脏毒性增加有关。本研究将阐明蒽环类药物对儿童ALL癌症幸存者心脏毒性的分子机制。

DESCRIPTION (provided by applicant): Long-term survivors of childhood cancer (LTS) have greater than an 8-fold increased risk of CV mortality compared to a healthy population 25 years after therapy. This risk increases progressively over time and appears related in part to anthracycline chemotherapy. Since 1:570 young adults in the US aged 20-45 by 2010 is projected to be a childhood cancer survivor and half will have had anthracycline therapy, the mechanism of this toxicity to prevent or treat it becomes critical to understand. Genetics (either natural genotypes or induced changes) may play a role in the susceptibility of anthracycline toxicity for each individual. In animal models of anthracycline cardiotoxicity, irreversible mitochondrial impairment, in part related to free-radical injury during therapy, leading to late cardiomyopathy is found but this has not been studied in humans. Mutations of the genes know to cause hemochromatosis (HFE mutations) may also lead to susceptibility to toxicity. In this application, Aim 1 will be to determine the frequency of mitochondrial DNA (mtDNA) mutations in pediatric acute lymphoblastic leukemia (ALL) survivors enrolled in the Dana Farber Cancer Institute Consortium. We will also determine if there are differences in mutation rates between children who received the cardioprotectant, dexrazoxane, versus those who did not. We will correlate the degree of mutations to other markers of cardiac function (echocardiographic measures and serum biomarkers of cardiac risk). Aim 2 will determine if HFE mutations are associated with greater long-term cardiotoxicity as measured by echocardiography and serum biomarkers. We will enroll a total of 200 ALL survivors enrolled in the DFCI ALL consortium who were enrolled in studies 91-001, 95-001, and 00-001. Only 50% will have received the cardioprotectant, dexrazoxane. mtDNA and HFE studies will be obtained >4 years from diagnosis with simultaneous evaluation of cardiac function via echocardiography and analysis of serum biomarkers of cardiac risk (lipids, proBNP, hsCRP, cTnT). We will determine: 1. If there is a higher frequency of mtDNA mutations associated with prior anthracycline treatment and if dexrazoxane is protective against these mutations 2. If mtDNA mutation relate to increased CV risk of cardiomyopathy, premature atherosclerosis; 3. If the HFE mutations are related to increased cardiotoxicity of anthracyclines. This study will elucidate the molecular mechanisms of anthracycline cardiotoxicity in pediatric ALL cancer survivors.