Genetic Mechanisms of Anthracycline Cardiotoxicity in Pediatric Cancer Survivors

描述（由申请方提供）：与治疗后25年的健康人群相比，儿童期癌症（LTS）长期存活者的CV死亡风险增加8倍以上。这种风险随着时间的推移逐渐增加，似乎部分与蒽环类药物化疗有关。由于到2010年，美国20-45岁的年轻人中有1：570预计将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。遗传学（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，发现了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。已知引起血色病的基因突变（HFE突变）也可能导致对毒性的敏感性。在本申请中，目标1是确定入选Dana Farber癌症研究所联盟的儿童急性淋巴细胞白血病（ALL）幸存者的线粒体DNA（mtDNA）突变频率。我们还将确定接受心脏保护剂右雷佐生的儿童与未接受的儿童之间的突变率是否存在差异。我们将把突变程度与其他心脏功能标志物（超声心动图测量和心脏风险的血清生物标志物）相关联。目标2将确定HFE突变是否与超声心动图和血清生物标志物测量的更大的长期心脏毒性相关。我们将入组DFCI ALL联盟中入组的共计200例ALL幸存者，这些患者入组了研究91-001、95-001和00-001。只有50%的人接受了心脏保护剂右雷佐生。mtDNA和HFE研究将在诊断后>4年获得，同时通过超声心动图评估心脏功能并分析心脏风险的血清生物标志物（脂质、proBNP、hsCRP、cTnT）。我们将确定：1。如果存在与既往蒽环类药物治疗相关的较高频率的mtDNA突变，并且右雷佐生是否对这些突变具有保护作用2。mtDNA突变是否与心血管性心肌病、早发动脉粥样硬化的风险增加有关; 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心脏毒性在儿童ALL癌症幸存者中的分子机制。

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.