(PQB-1) Telomere maintenance defects and thyroid second cancer in childhood cancer survivors

(PQB-1) 儿童癌症幸存者的端粒维持缺陷和甲状腺第二癌

• 批准号: 8876292
• 负责人: Maria Monica Gramatges
• 金额: $ 38.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876292
• 关键词: Ablation; Achievement; Address; Age; Biological Assay; Biology; Cancer Survivor; Childhood Cancer Survivor Study; Chromosomes; DNA Damage; DNA Sequence; Data; Defect; Diagnosis; Female; Gender; General Population; Genetic; Genetic Markers; Genomic Instability; Genotype; Goals; Health; Histologic; In Vitro; Late Effects; Length; Leukocytes; Lymphocyte Subset; Malignant Childhood Neoplasm; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Missense Mutation; Modality; Modeling; Morbidity - disease rate; Mutation; Nodule; Outcome; Palpation; Pediatric Oncology Group; Population; Predictive Value; Prevention strategy; Preventive; Publishing; Radiation; Radioactive Iodine; Reporting; Reproducibility; Resources; Risk; Risk Factors; Role; Sampling; Second Primary Cancers; Sensitivity and Specificity; Single Nucleotide Polymorphism; Study Subject; Survival Rate; Survivors; Target Populations; Techniques; Telomerase; Telomere Maintenance; Telomere Maintenance Gene; Telomere Shortening; Testing; Therapeutic; Thyroid Gland; Ultrasonography; advanced disease; base; biobank; cancer risk; cancer therapy; childhood cancer survivor; cohort; cost effective; genetic risk factor; genome-wide; high risk; improved; non-genetic; predictive modeling; public health relevance; screening; telomere; tool

 DESCRIPTION (provided by applicant): Despite recent improvements in childhood cancer survival, survivors remain at increased risk for late effects such as subsequent malignant neoplasms (SMNs). Thyroid SMN is among the most prevalent SMNs in childhood cancer survivors, and advanced disease is associated with significant treatment-related morbidities. A current risk prediction model for thyroid SMN, developed for the Childhood Cancer Survivor Study (CCSS) cohort, includes only non-genetic risk factors, such as female gender, age at diagnosis, and therapeutic radiation exposure. Short telomeres are a genetic risk factor for primary cancer risk, but the impact of telomere length upon SMN is just emerging. The PI has conducted one of the first studies addressing this question, with recently published results showing short telomeres associated with thyroid SMN in the CCSS cohort. Because radiation contributes to telomere shortening, we hypothesize that radiation-exposed childhood cancer survivors with underlying genetic defects in telomere maintenance are at highest risk for developing thyroid SMN. Our goal is to elucidate telomere biology defects underlying risk for thyroid SMN using CCSS genotyping data and biorepository samples. We will use our results to improve the existing thyroid SMN risk prediction model in the CCSS cohort, and then test our model for reproducibility in a distinct Children's Oncology Group (COG) study. We will test our hypothesis in three Specific Aims (SA). SA1 leverages existing CCSS genotyping data to determine if single nucleotide polymorphisms (SNPs) associated with impaired telomere maintenance distinguish survivors with thyroid SMN compared with survivors without SMN, and contribute to telomere length as estimated by qPCR. SA2 asks if rare and deleterious mutations in telomere maintenance genes are enriched in survivors with thyroid SMN as compared with survivors without SMN and cancer-naive controls. Mutations identified will be tested for functional impact in vitro, using established telomerase activity assays and flow FISH for telomere length in lymphocyte subsets. SA3 will extend a previously validated risk prediction model for thyroid SMN, measuring the added impact of genetic factors including (1) top telomere maintenance SNPs associated with SMN in the CCSS, (2) top telomere maintenance SNPs found in SA1, and (3) SNPs previously associated with telomere length. The model will then be tested in a distinct COG survivor study. We expect a risk prediction model inclusive of genetic factors to improve our ability to identify childhood cancer survivors at highest risk for thyroid SMN. At-risk survivors are now screened for thyroid SMN by thyroid gland palpation, a technique that is relatively insensitive. We expect our model to justify use of more sensitive screening modalities, such as ultrasound, in targeted populations, thereby substantially reducing the impact of a prevalent SMN upon non-relapse related morbidities. By establishing a role for genetic risk factors such as telomere maintenance defects in predicting late effects such as thyroid SMN, this study has the potential to transform how we approach risk determination for late effects common to childhood cancer survivors.

 描述（由适用提供）：尽管儿童癌症的存活最近有所改善，但幸存者仍处于延迟影响（例如随后的恶性肿瘤（SMN））的风险增加。甲状腺SMN是儿童癌症生存中最普遍的SMN之一，晚期疾病与与治疗相关的严重病态有关。甲状腺SMN的当前风险预测模型是为儿童癌症幸存者研究（CCSS）队列开发的，仅包括非遗传危险因素，例如女性性别，诊断年龄和热辐射暴露。短端粒是原发性癌症风险的遗传危险因素，但是端粒长度对SMN的影响只是出现。 PI已经进行了解决这个问题的第一项研究之一，最近发布的结果表明，CCSS队列中与甲状腺SMN相关的短端粒。由于辐射有助于端粒缩短，因此我们假设暴露于辐射的儿童癌症存活率具有潜在的端粒遗传缺陷，在端粒维持中的遗传缺陷是发展甲状腺SMN的最高风险。我们的目标是阐明使用CCSS基因分型数据和生物验证样本的甲状腺SMN的端粒生物学缺陷。我们将使用结果来改善CCSS队列中现有的甲状腺SMN风险预测模型，然后在不同的儿童肿瘤学组（COG）研究中测试我们的可重复性模型。我们将在三个特定目标（SA）中检验我们的假设。 SA1利用现有的CCSS基因分型数据来确定与端粒维持受损相关的单个核苷酸多态性（SNP）是否与没有SMN的存活相比，具有甲状腺SMN的生存区分，并促进了由qPCR估计的端粒长度。 SA2询问与没有SMN和癌症对照的幸存者相比，端粒维持基因中的罕见和删除的突变是否富含甲状腺SMN的幸存者。使用已建立的端粒活性评估和流动鱼类的淋巴细胞亚群中端粒长度，将测试所鉴定的突变体外功能影响。 SA3将扩展甲状腺SMN的先前验证的风险预测模型，测量遗传因素的附加影响，包括（1）CCS中与SMN相关的顶级端粒维持SNP，（2）SA1中发现的顶级端粒维护SNP，以及（3）先前与端粒长度相关的SNP。然后将在一项独特的COG生存研究中测试该模型。我们预计，包括遗传因素的风险预测模型可以提高我们鉴定甲状腺SMN风险最高风险的儿童癌症生存的能力。现在，通过甲状腺触诊为甲状腺SMN筛选了高危生存，这是一种相对不敏感的技术。我们希望我们的模型能够证明使用更敏感的筛查方式，例如超声，在目标人群中，从而大大降低了普遍的SMN对非释放相关的病态性的影响。通过确定诸如端粒维持缺陷等遗传危险因素在预测甲状腺SMN等后期作用中的作用，这项研究有可能改变我们如何对儿童期癌症生存常见的后期影响进行危险确定。