Genetics of risk of chemotherapy-induced cardiotoxicity in cancer survivors

癌症幸存者化疗引起的心脏毒性风险的遗传学

• 批准号: 8726353
• 负责人: PETER DEMANT
• 金额: $ 21.68万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8726353
• 关键词: Adult; Affect; Aftercare; Alleles; Anthracyclines; Antineoplastic Agents; Biological Assay; Biological Markers; Biopsy; Blood; Cancer Survivor; Cancer-Predisposing Gene; Cardiotoxicity; Child; Complement; Computer Simulation; Congenic Mice; Congenic Strain; Congestive Heart Failure; Diagnostic; Disease; Disease susceptibility; Dose; Doxorubicin; Drug Interactions; Drug Kinetics; ERBB2 gene; Exhibits; Family; Frequencies; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genetic Markers; Genetic Risk; Global Change; Heart; Heart Injuries; Heart Transplantation; Heating; Hematologic Neoplasms; Heterogeneity; Hodgkin Disease; Homologous Gene; Human; Hybrids; Inbred BALB C Mice; Individual; Individual Differences; Inherited; Lead; Liver; Malignant Childhood Neoplasm; Maps; Modification; Molecular Profiling; Morbidity - disease rate; Mouse Strains; Mus; Myocardial; Non-Hodgkin' s Lymphoma; Organism; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Predisposition; Prevention; Prevention therapy; Process; Processed Genes; Reaction; Recombinants; Risk; Risk Assessment; Role; Scheme; Site; Solid Neoplasm; Staging; Survival Rate; Survivors; Susceptibility Gene; Testing; Time; Tissues; Toxic effect; Variant; adult leukemia; base; chemotherapy; childhood cancer survivor; clinically relevant; experience; follow-up; genetic analysis; genetic linkage analysis; human disease; improved; insight; irinotecan; malignant breast neoplasm; mortality; mouse model; novel; novel strategies; outcome forecast; prevent; public health relevance; resistant strain; tool

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.

描述（由申请人提供）：我们将构建一系列标记物，以评估癌症幸存者中蒽环类诱导的心脏毒性（ACT）的风险，以及用于分析其发病机理的发现工具。蒽环类药物（例如阿霉素）在治疗血液系统恶性肿瘤（包括霍奇金和非霍奇金淋巴瘤）方面非常有效，许多童年时期的癌症在其中负责生存率的显着增加，以及在HER2+乳房中以及HER2+乳腺癌和成人的其他实心肿胀中。但是，在50％的幸存者中，它们会引起亚临床心脏损伤，可以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重大贡献，因此对行为风险的预测可以强烈改善其 长期预后通过个性化治疗和治疗后随访，而对ACT发病机理的更好理解可能会导致其预防和治疗的新颖手段。我们将使用专门的小鼠模型来开发大量的ACT风险遗传标记，并研究ACT发病机理的个体异质性。 遗传对ACT发病机理的影响是由大量耐受性的阿霉素剂量180-800 mg/m2的累积范围表明，并且通过基因CBR3和SLC28A3对ACT风险的影响，尽管由于许多其他基因的参与，它们无法预测个体风险。因此，我们将绘制小鼠中新型的行动敏感性（ACTS）基因，然后分析其人类同源物。我们将使用小鼠重组先兆（RC）菌株 - 一种强大的映射工具，使我们能够检测到> 130个新型疾病易感基因，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，它们都是新的，并且与已知的伊立替康处理基因不同。对阿霉素毒性易感性的初步测试表明，RC菌株之间存在显着差异，表明我们可以检测到30-40个新型ACTS基因。作为对它们在人类中的作用的初步测试，我们将比较这些基因的人类同源物的等位基因在最坏的行为中影响了接受心脏移植和匹配的对照的人类。由于ACT的发病机理仅部分清晰，并且其个体差异尚不清楚，因此我们将产生具有不同ACT基因的小鼠线，这些基因将作为研究ACT发病机理的永久工具，并将测试不同作用基因对多Xorubibicin preated小鼠心脏中全球基因表达模式的影响。对于未来在人类中的类似测试，我们将从诊断性心肌活检中收集RNA。这将有强大的前景来揭示影响行为的新途径，并为在小鼠和人类中的单个行为发病机理定义开辟道路。