Genetics of risk of chemotherapy-induced cardiotoxicity in cancer survivors

描述（由申请人提供）：我们将构建一个广谱的标记物，用于评估癌症幸存者中蒽环类药物诱导的心脏毒性（ACT）的风险，并构建一个发现工具，用于分析个体患者的发病机制。蒽环类药物（如阿霉素）在治疗血液恶性肿瘤（包括霍奇金淋巴瘤和非霍奇金淋巴瘤）和许多儿童癌症方面非常有效，其中它们是存活率显著增加的重要部分，以及HER 2+乳腺癌和成人的其他实体瘤。然而，在50%的幸存者中，它们会导致亚临床心脏损伤，并可能发展为无法治愈的充血性心力衰竭。由于ACT对癌症幸存者的发病率和死亡率有显着影响，因此预测ACT风险可以大大改善他们的生活质量。 通过个体化治疗和治疗后随访可以预测ACT的长期预后，而更好地了解ACT的发病机制可能会导致其预防和治疗的新手段。我们将使用一个专门的小鼠模型来开发一套新的ACT风险遗传标记，并研究ACT发病机制的个体异质性。 遗传对ACT发病机制的影响由耐受的累积阿霉素剂量180 - 800 mg/m2的大范围和基因CBR 3和SLC 28 A3对ACT风险的影响指示，尽管它们不能预测个体风险，因为涉及许多其他基因。因此，我们将在小鼠中绘制新的ACT敏感性（ACT）基因，然后分析它们的人类同源物。我们将使用小鼠重组同源（RC）菌株-一种强大的作图工具，使我们能够检测超过130个新的疾病易感基因，并表明它们的同源物可以影响人类疾病。它还检测到15个影响伊立替康毒性风险的基因，所有这些基因都是新的，与已知的伊立替康加工基因不同。阿霉素毒性敏感性的初步测试显示RC菌株之间存在显着差异，表明我们可以检测到30 - 40个新的resistance基因。作为它们在人类中作用的初步测试，我们将比较这些基因在接受心脏移植的受ACT影响最严重的人和匹配对照中的人类同源物的等位基因。由于ACT的发病机制仅部分清楚，其个体差异尚不清楚，我们将产生具有不同β-内酰胺酶基因的小鼠品系，其将作为研究ACT发病机制的永久工具，并将测试不同β-内酰胺酶基因对多柔比星治疗小鼠心脏中的全局基因表达模式的影响，以及未来的额外功能测试。为了将来在人类中进行类似的测试，我们将从诊断性心肌活检中收集RNA。这将有很强的前景，以发现新的途径影响ACT和开辟的方式定义个别ACT发病机制在小鼠和人类。

DESCRIPTION (provided by applicant): We will construct a broad spectrum of markers for assessment of risk of anthracycline-induced cardiotoxicity (ACT) in cancer survivors, and a discovery tool for analysis of its pathogenesis in individual patients. Anthracyclines (such as doxorubicin) are highly effective in treatment of hematologic malignancies (including Hodgkin and non-Hodgkin lymphoma), and many childhood cancers where they are responsible for a significant part of the spectacular increase in survival rates, as well as in HER2+ breast cancers and other solid tumors in adults. However, in 50% of survivors they cause subclinical heart injury that can progress into incurable congestive heart failure. As ACT contributes significantly to morbidity and mortality of cancer survivors, prediction of ACT risk could strongly improve their long term prognosis by personalizing the therapy and post-treatment follow-up, while a better understanding of ACT's pathogenesis could lead to novel means of its prevention and therapy. We will use a specialized mouse model to develop a large set of new genetic markers of ACT risk and investigate individual heterogeneity of ACT pathogenesis. Genetic influence on ACT pathogenesis is indicated by the large range of tolerated cumulative doxorubicin dose 180 - 800 mg/m2 and by impact of genes CBR3 and SLC28A3 on ACT risk, although they cannot predict individual risk, due to involvement of numerous other genes. We will therefore map novel ACT-susceptibility (ACTS) genes in mice and then analyze their human homologues. We will use mouse recombinant congenic (RC) strains - a powerful mapping tool that allowed us to detect >130 novel disease susceptibility genes and to show that their homologues can affect human disease. It also detected 15 genes affecting risk of irinotecan toxicity, all of them new and different from known irinotecan-processing genes. Preliminary tests of susceptibility to doxorubicin toxicity revealed significant differences among RC strains, indicating that we can detect 30 - 40 novel ACTS genes. As a preliminary test of their role in humans, we will compare the alleles of human homologues of these genes in the worst ACT affected humans who received heart transplant and matched controls. As the pathogenesis of ACT is only partly clear and its individual differences are not known, we will produce mouse lines with different ACTS genes that will serve as a permanent tool for study of ACT pathogenesis and will test the impact of different ACTS genes on global gene expression patterns in hearts of doxorubicin-treated mice and in future additional functional tests. For future similar tests in humans we will collect RNAs from diagnostic myocardial biopsies. This will have strong prospects to uncover novel pathways influencing ACT and open the way for definition of individual ACT pathogenesis in mice and humans.