Late Effects of Treatment in Wilms Tumor Survivors and Offspring

描述（由申请人提供）：本提案旨在研究接受Wilms肿瘤（WT）治疗的儿童的长期健康状况，并监测其后代的癌症和出生缺陷。该研究基于国家肾母细胞瘤研究（NWTS）进行的5项临床试验之一，在1969-2002年期间招募了9236名患者，这是一项独特且描述良好的队列研究。NWTS研究3-5制定了治疗方案，今天作为“标准治疗”对绝大多数患者实施。通过这种疗法，90%的WT患儿被治愈。然而，幸存者面临疾病或治疗延迟并发症的风险，这可能会损害他们的生活质量。由于该病通常发生在儿童早期，因此需要数十年的随访才能了解成年幸存者的后果。针对四种危及生命的疾病：继发性恶性肿瘤；充血性心力衰竭；终末期肾病（ESRD）；以及限制性肺病。大多数情况可通过检查医疗记录得到证实。具体目标是根据治疗、疾病和宿主因素确定NWTS-3-5中每一种疾病的高风险患者的新亚组。例如，ESRD高危患者可以考虑进行肾保留手术。从NWTS-5患者身上收集的生物样本将用于验证WT1基因突变不仅在儿童时期易患WT，而且在青春期和成年期易患ESRD的假设。系统地收集出生体重、先天性异常、肾源性病变、组织学类型、放疗和化疗剂量等信息，构建ESRD的风险函数，并研究对充血性心力衰竭和继发性恶性肿瘤的治疗效果是否因Wilms肿瘤的生物学亚型而不同。该研究将评估女性患者卵巢功能衰竭的发生率，以及男性患者伴侣的活产率和妊娠并发症的风险。

DESCRIPTION (provided by applicant): This proposal is to study the long term health of children treated for Wilms tumor (WT), and to monitor their offspring for cancer and birth defects. The study is based in the unique and well described cohort of 9,236 patients enrolled during 1969-2002 on one of 5 clinical trials conducted by the National Wilms Tumor Study (NWTS). NWTS studies 3-5 developed treatment protocols that today are administered as "standard therapy" to the vast majority of patients. With this therapy, 90% of children with WT are cured. Survivors, however, are at risk for delayed complications of their disease or its treatment that may compromise their quality of life. Since the disease typically occurs in early childhood, many decades of follow-up are required to appreciate the consequences for adult survivors. Four life-threatening conditions are targeted: secondary malignant neoplasms; congestive heart failure; end stage renal disease (ESRD); and restrictive pulmonary disease. Most occurrences are validated by examination of medical records. Specific goals are to identify new subgroups of patients from NWTS-3-5 at high risk for each condition based on treatment, disease and host factors. Patients at high risk for ESRD, for example, may be considered for renal sparing surgery. Biological samples collected from patients on NWTS-5 will be used to test the hypothesis that mutations in the WT1 gene not only predispose to WT in childhood but also to ESRD in adolescence and adulthood. Systematically collected information on birth weights, congenital anomalies, nephrogenic rests, histologic type, and on radiation and chemotherapy doses will be used to construct risk functions for ESRD and to investigate whether treatment effects on congestive heart failure and secondary malignant neoplasms differ according to the biological subtype of Wilms tumor. The study will estimate rates of ovarian failure in female patients and rates of live birth and risks of pregnancy complications in partners of male patients. Heritability and recurrence risks of WT, together with the frequency of birth defects in the next generation, will be estimated through follow-up of a unique cohort of patient offspring.