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）：我们将构建广泛的标记物，用于评估癌症幸存者中蒽环类药物引起的心脏毒性（ACT）的风险，以及用于分析个体患者发病机制的发现工具。蒽环类药物（如多柔比星）对于治疗血液系统恶性肿瘤（包括霍奇金淋巴瘤和非霍奇金淋巴瘤）以及许多儿童癌症以及 HER2+ 乳腺癌的存活率的大幅提高起到了重要作用。成人癌症和其他实体瘤。然而，50% 的幸存者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，预测 ACT 风险可以极大地改善他们的生存状况。 通过个性化治疗和治疗后随访来改善长期预后，而更好地了解 ACT 的发病机制可能会带来新的预防和治疗方法。我们将使用专门的小鼠模型来开发大量新的 ACT 风险遗传标记，并研究 ACT 发病机制的个体异质性。 ACT 发病机制的遗传影响表现为大范围的阿霉素累积剂量 180 - 800 mg/m2 以及基因 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，我们将绘制小鼠体内新的 ACT 易感性 (ACTS) 基因图谱，然后分析它们的人类同源物。我们将使用小鼠重组同源 (RC) 品系，这是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，并证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且不同于已知的伊立替康处理基因。对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 ACTS 基因。作为对它们在人类中作用的初步测试，我们将比较接受心脏移植和匹配对照的受 ACT 影响最严重的人类中这些基因的人类同源物的等位基因。由于ACT的发病机制尚不明确，且个体差异尚不清楚，我们将培育具有不同ACTS基因的小鼠品系，作为研究ACT发病机制的永久工具，并测试不同ACTS基因对整体基因的影响阿霉素治疗小鼠心脏中的表达模式以及未来其他功能测试中的表达模式。对于未来类似的人类测试，我们将从诊断性心肌活检中收集 RNA。这将很有可能揭示影响 ACT 的新途径，并为小鼠和人类个体 ACT 发病机制的定义开辟道路。