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: 8571654
• 负责人: PETER DEMANT
• 金额: $ 19.61万
• 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/8571654
• 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)：我们将构建一系列广泛的标记物，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，并构建一种用于分析其在个别患者中的发病机制的发现工具。在血液系统恶性肿瘤(包括霍奇金淋巴瘤和非霍奇金淋巴瘤)和许多儿童癌症中，它们是显著提高存活率的主要原因，而在成人HER2+乳腺癌和其他实体肿瘤中，蒽环类药物(如阿霉素)非常有效。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著影响，预测ACT的风险可以极大地改善他们的病情 通过个体化治疗和治疗后的随访，可以获得长期的预后，而对ACT的发病机制的更好的理解可以为其预防和治疗提供新的手段。我们将使用专门的小鼠模型来开发一大套新的ACT风险的遗传标记，并调查ACT发病机制的个体异质性。基因对ACT发病的影响表现为耐受阿霉素累积剂量180-800 mg/m2的大范围，以及CBR3和SLC28A3基因对ACT风险的影响，尽管由于涉及许多其他基因，它们不能预测个体风险。因此，我们将在小鼠中定位新的ACT易感性(ACTs)基因，然后分析它们的人类同源基因。我们将使用小鼠重组同源(RC)菌株，这是一种强大的图谱工具，使我们能够检测&gt；130新的疾病易感基因，并表明它们的同源基因可以影响人类疾病。它还检测到15个影响伊立替康中毒风险的基因，所有这些基因都是新的，不同于已知的伊立替康加工基因。初步的阿霉素敏感性试验显示，不同的RC菌株之间存在显著差异，表明我们可以检测到30-40个新的ACTS基因。作为它们在人类中作用的初步测试，我们将在接受心脏移植的最严重的ACT患者和匹配的对照组中比较这些基因的人类同源基因的等位基因。由于ACT的发病机制尚不完全清楚，其个体差异尚不清楚，我们将培育具有不同ACT基因的小鼠品系，作为研究ACT发病机制的永久工具，并将在未来的额外功能测试中测试不同的ACT基因对阿霉素治疗小鼠心脏整体基因表达模式的影响。为了将来在人类身上进行类似的测试，我们将从诊断心肌活检中收集RNA。这将对发现影响ACT的新途径具有很强的前景，并为确定ACT在小鼠和人类中的个体发病机制开辟道路。