(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（由申请人提供）：尽管儿童癌症生存率最近有所改善，但幸存者的晚期效应（如随后的恶性肿瘤（SMN））风险仍然增加。甲状腺SMN是儿童癌症幸存者中最常见的SMN之一，晚期疾病与显著的治疗相关发病率相关。目前为儿童癌症幸存者研究（CCSS）队列开发的甲状腺SMN风险预测模型仅包括非遗传风险因素，如女性性别、诊断时年龄和治疗性辐射暴露。短端粒是原发性癌症风险的遗传风险因素，但端粒长度对SMN的影响才刚刚出现。PI进行了解决该问题的首批研究之一，最近发表的结果显示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，我们假设，暴露于辐射的儿童癌症幸存者与潜在的遗传缺陷，端粒的维护是在发展甲状腺SMN的风险最高。我们的目标是利用CCSS基因分型数据和生物库样本阐明甲状腺SMN风险的端粒生物学缺陷。我们将使用我们的结果来改善CCSS队列中现有的甲状腺SMN风险预测模型，然后在一项不同的儿童肿瘤学组（COG）研究中测试我们的模型的可重复性。 我们将在三个特定目标（SA）中测试我们的假设。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核苷酸多态性（SNP）是否可区分甲状腺SMN幸存者与无SMN幸存者，并有助于qPCR估计的端粒长度。SA2询问与没有SMN的幸存者和癌症初治对照相比，甲状腺SMN幸存者中端粒维持基因的罕见和有害突变是否富集。将使用已建立的端粒酶活性测定和流式FISH检测淋巴细胞亚群中的端粒长度，在体外测试鉴定的突变的功能影响。SA3将扩展先前验证的甲状腺SMN风险预测模型，测量遗传因素的额外影响，包括（1）CCSS中与SMN相关的最高端粒维持SNP，（2）SA1中发现的最高端粒维持SNP，以及（3）先前与端粒长度相关的SNP。然后将在一项不同的COG幸存者研究中对该模型进行测试。 我们期望包括遗传因素在内的风险预测模型能够提高我们识别甲状腺SMN风险最高的儿童癌症幸存者的能力。目前，高危幸存者通过甲状腺触诊筛查甲状腺SMN，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在目标人群中使用更敏感的筛查方式（如超声）是合理的，从而大大降低了流行SMN对非复发相关疾病的影响。通过建立遗传风险因素（如端粒维持缺陷）在预测甲状腺SMN等晚期效应中的作用，这项研究有可能改变我们如何确定儿童癌症幸存者常见的晚期效应的风险。