Testicular effects of modern chemotherapy regimens in osteosarcoma survivors

 描述(由申请人提供)：男性儿童和青少年(Aya)癌症幸存者面临的最重要挑战之一是癌症化疗的生殖毒性。顺铂和异环磷酰胺构成了一些最常见的儿童和青年癌症化疗的支柱，但关于顺铂的作用，以及不含环磷酰胺的异环磷酰胺对儿童癌症和非生殖细胞癌症男性幸存者精子发生和类固醇生成的影响，尚缺乏了解。DNA甲基化的改变可能是这些药物影响睾丸功能的机制之一。更好地了解这些影响将有助于识别高危患者，并为儿科和AYA癌症治疗方案制定更好的睾丸毒性预防策略。本研究将全面评估顺铂联合异环磷酰胺或不联合异环磷酰胺对接受现代化疗治疗骨肉瘤的儿童和AYA幸存者的精子发生和类固醇生成的影响。具体地说，我们的目标是：1)确定接受或不使用异环磷酰胺的顺铂治疗的男性骨肉瘤幸存者与没有癌症病史的男性对照组相比，不育和/或精子生成和类固醇生成的生物标志物是否不同；2)评估用于治疗骨肉瘤的顺铂是否与精子DNA甲基化模式相关。骨肉瘤幸存者将从两个COG治疗试验中招募 [COG AOST0331和INT0133(CCG7921和POG9351)]，以及通过基于地址的抽样确定和招募的控制措施。受试者将完成问卷调查，并通过邮寄协议提供血液、唾液和精液样本。血液样本将分析睾酮、促黄体生成素、黄体生成素、抑制素B；从唾液中提取并储存基因组DNA，用于未来化疗药物储存代谢中宿主遗传变异的研究；精子DNA将使用全基因组甲基化DNA免疫沉淀进行分析，然后进行下一代测序。组建的团队和联盟汇集了泌尿学、男科学、肿瘤学、流行病学、生物统计学和表观基因组学方面的多学科专业知识。拟议研究的完成将是向接受类似方案的男性童年和Aya癌症患者告知其治疗的不利影响以及确定将受益于有针对性的保留生育能力战略的高危群体的重要一步。

 DESCRIPTION (provided by applicant): Among the most important challenges faced by male childhood and adolescent and young adult (AYA) cancer survivors is the reproductive toxicity of cancer chemotherapy. Cisplatin and Ifosfamide form the backbone of chemotherapy for some of the most common childhood and young adult cancers, but there is a gap in knowledge regarding the effects of cisplatin, and the effects of ifosfamide without cyclophosphamide, on spermatogenesis and steroidogenesis in male AYA survivors of childhood cancer and non-germ cell cancer populations. DNA methylation changes are a possible mechanism of action of these drugs on testicular function. A better understanding of these effects will allow for identificationof high risk patients and better prevention strategies for testicular toxicity to be developed for pediatric and AYA cancer treatment protocols. This study will comprehensively evaluate the effects of cisplatin with or without ifosfamide on spermatogenesis and steroidogenesis among childhood and AYA survivors treated with modern chemotherapies for osteosarcoma. Specifically, our aims are: 1) Determine whether infertility and/or biomarkers of spermatogenesis and steroidogenesis differ in male osteosarcoma survivors treated with cisplatin with or without ifosfamide compared to male controls without a history of cancer; 2) Evaluate whether cisplatin with or without ifosfamide for the treatment of osteosarcoma is associated with sperm DNA methylation patterns. Osteosarcoma survivors will be recruited from two COG therapeutic trials [COG AOST0331 and INT0133 (CCG7921 and POG9351)], and controls identified and recruited through address-based sampling. Subjects will complete questionnaires and provide blood, saliva, and semen samples through a mail protocol. Blood samples will be analyzed for testosterone, FSH, LH, Inhibin B; genomic DNA extracted from saliva and stored for future studies of host genetic variation in metabolism of chemotherapeutic drugs storage; and sperm DNA will be assayed using genome-wide methylated DNA immunoprecipitation followed by next generation sequencing. The assembled team and consortium brings together multi-disciplinary expertise in urology, andrology, oncology, epidemiology, biostatistics, and epigenomics. Completion of the proposed research will be a major step towards informing male childhood and AYA cancer patients receiving similar regimens about the adverse effects of their treatment and towards identifying high risk groups that would benefit from targeted strategies for fertility preservation.