Testicular effects of modern chemotherapy regimens in osteosarcoma survivors

 描述（由申请人提供）：男性儿童、青少年和青年（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。顺铂和异环磷酰胺是一些最常见的儿童和年轻成人癌症的化疗支柱，但关于顺铂的影响，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人群的男性AYA幸存者的精子发生和类固醇生成的影响，存在知识空白。DNA甲基化变化是这些药物对睾丸功能的可能作用机制。更好地了解这些影响将有助于识别高风险患者，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。本研究将全面评价顺铂联合或不联合异环磷酰胺对接受现代骨肉瘤化疗的儿童和AYA幸存者精子发生和类固醇生成的影响。具体而言，我们的目标是：1）确定与无癌症史的男性对照相比，接受顺铂联合或不联合异环磷酰胺治疗的男性骨肉瘤幸存者的不育和/或精子发生和类固醇生成的生物标志物是否不同; 2）评价顺铂联合或不联合异环磷酰胺治疗骨肉瘤是否与精子DNA甲基化模式相关。将从两项COG治疗试验中招募骨肉瘤幸存者 [COG AOST 0331和INT 0133（CCG 7921和POG 9351）]，通过基于地址的采样识别和招募对照。受试者将填写问卷，并通过邮寄方案提供血液、唾液和精液样本。将分析血液样本中的睾酮、FSH、LH、抑制素B;从唾液中提取基因组DNA并储存，用于未来研究化疗药物储存代谢中的宿主遗传变异;将使用全基因组甲基化DNA免疫沉淀法分析精子DNA，然后进行下一代测序。该团队和联盟汇集了泌尿学、男科、肿瘤学、流行病学、生物统计学和表观基因组学等多学科的专业知识。完成拟议的研究将是向接受类似治疗方案的男性儿童和AYA癌症患者告知其治疗的不良影响以及确定将受益于有针对性的生育力保护策略的高风险群体迈出的重要一步。

 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.