Outcomes in AYA survivors of pediatric medulloblastoma.

小儿髓母细胞瘤 AYA 幸存者的结果。

• 批准号: 10659122
• 负责人: TRICIA Z KING
• 金额: $ 47.03万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659122
• 关键词: Adaptive Behaviors; Adolescent and Young Adult; Age; Algorithms; Area; Brain Neoplasms; Caregivers; Caring; Cerebellum; Characteristics; Childhood; Childhood Brain Neoplasm; Childhood Medulloblastomas; Clinical; Clinical Markers; Clinical Research; Cognitive; Collaborations; DNA Sequence Alteration; DNA sequencing; Development; Disease susceptibility; Dose; Drug Design; Early identification; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Transcription; Genotype; Health; Heterogeneity; Impaired cognition; Individual; Individual Differences; Infrastructure; Intervention; Late Effects; Life; Literature; Machine Learning; Malignant Neoplasms; Measures; Methods; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Mutation; NCI-Designated Cancer Center; Neighborhoods; Neuronal Plasticity; Outcome; Outcome Measure; Oxidative Stress; Pathway interactions; Patient-Focused Outcomes; Population; Precision Medicine Initiative; Prevention; Proteins; Quality of life; RNA analysis; Race; Readiness; Recording of previous events; Regimen; Research; Research Design; Resources; Risk; Risk Factors; SHH gene; Schools; Severities; Single Nucleotide Polymorphism; Site; Surveillance Modeling; Survivors; Tumor Subtype; Variant; Weight; analysis pipeline; biopsychosocial; candidate validation; caregiving; chemoradiation; childhood cancer survivor; clinical risk; clinically relevant; cognitive ability; cohort; deprivation; design; disability; experience; family caregiving; folic acid metabolism; genetic variant; health related quality of life; high risk; improved; indexing; individualized medicine; innovation; interest; medulloblastoma; molecular subtypes; neuroinflammation; neurotoxic; neurotransmission; outcome prediction; peer; precision medicine; preemptive intervention; prevent; preventive intervention; prophylactic; radiation risk; recruit; repaired; sex; socioeconomic adversity; standardize measure; survivorship; tool; transcriptome sequencing; treatment response; tumor

Abstract This clinical research identifies the robust factors that contribute to cognitive outcomes in pediatric, adolescent, and young adult survivors (PAYAS) of medulloblastoma (MB) brain tumors located in the cerebellum. Pediatric brain tumor survivors are at increased risk of cognitive impairment (CI) and have substantial likelihood of poor health and disability relative to those who do not have a cancer history, and relative to survivors who did not have to undergo lifesaving neurotoxic chemoradiation treatment. However, individual differences in cognitive outcomes among PAYAS of MB are diverse and wide ranging, even when the most likely clinical contributors are the same (i.e., age at treatment, chemoradiation level of risk, MB tumor subtype). This led our team to examine genetic diatheses and other contributors that may explain the wide range of outcomes, from mild to severe CI. In addition to genetics, there is a need to fill important gaps in the research to date to identify both clinical risk factors and environmental resources that identify those at greatest risk of CI. This multisite project at NCI-designated cancer centers in GA, AL, and OH will examine multifactorial environmental resources (e.g., neighborhood socioeconomic adversity, material hardships, caregiving capacity, and school quality), clinical factors (e.g., age at treatment, chemoradiation level of risk, MB tumor type), and individual genetic diathesis (i.e., candidate single nucleotide polymorphism variants (SNPs)). First, in Aim 1, the study will examine each of the three domains independently using state of the art methods and innovative analyses to identify the best predictors of CI. In other populations, polygenetic risk scores (PRS) have provided a stronger prediction of outcomes than single SNPs alone. Therefore, within the genetic diathesis domain, we will examine targeted SNPs and neighboring interactive mutations to create a robust PRS utilizing machine learning tools that weights SNPs regulating RNA expression associated with CI, and incorporates known functional impact of epigenetics, transcriptions and proteins. Second, in Aim 2, we will create a multi-domain risk algorithm, using the most sensitive predictors of CI across the three domains (i.e., clinical risks, environmental resources, and genetic diathesis). This empirically derived risk algorithm will inform precision medicine, by identifying conditions for risk-adapted chemoradiation treatment and prophylactic interventions to prevent, mitigate and manage CI. Consistent with the STAR Act of 2018 and the Precision Medicine Initiative, these findings will allow for early identification of individuals at risk for CI and provide targets for treatments in order to improve overall quality of life and adaptive functioning in PAYAS of childhood cancer.

抽象的 这项临床研究确定了影响认知结果的强有力因素 髓母细胞瘤 (MB) 脑肿瘤的儿科、青少年和年轻成年幸存者 (PAYAS) 位于小脑。儿童脑肿瘤幸存者认知障碍的风险增加 损害（CI），并且相对于那些人来说，健康状况不佳和残疾的可能性很大 没有癌症病史，并且相对于无需接受救生的幸存者 神经毒性放化疗治疗。然而，认知结果存在个体差异 即使最有可能的临床贡献者，MB 的 PAYAS 也是多种多样且范围广泛的 相同（即治疗年龄、放化疗风险水平、MB 肿瘤亚型）。这导致我们 团队检查遗传素质和其他因素，这些因素可以解释广泛的 结果，从轻度到重度 CI。除了遗传学之外，还需要填补以下方面的重要空白： 迄今为止的研究旨在确定临床风险因素和环境资源 那些最有 CI 风险的人。这个多站点项目位于佐治亚州、阿拉巴马州 NCI 指定的癌症中心， OH 将检查多因素环境资源（例如，社区社会经济 逆境、物质困难、照顾能力和学校质量）、临床因素（例如年龄 治疗、放化疗风险水平、MB 肿瘤类型）和个体遗传素质（即 候选单核苷酸多态性变体（SNP））。首先，在目标 1 中，该研究将检查 三个领域中的每一个领域都独立地使用最先进的方法和创新分析 确定 CI 的最佳预测因子。在其他人群中，多基因风险评分（PRS） 比单独使用单个 SNP 提供了更强的结果预测。因此，在遗传基因范围内 素质域，我们将检查目标 SNP 和邻近的相互作用突变以创建 强大的 PRS，利用机器学习工具对调节 RNA 表达的 SNP 进行加权 与 CI 相关，并结合了表观遗传学、转录和已知的功能影响 蛋白质。其次，在目标 2 中，我们将创建一个多域风险算法，使用最敏感的风险算法 跨三个领域（即临床风险、环境资源和遗传）的 CI 预测因子 素质）。这种根据经验得出的风险算法将通过识别 风险适应放化疗治疗和预防性干预措施的条件， 减轻和管理 CI。符合 2018 年 STAR 法案和精准医疗 倡议，这些发现将有助于及早识别有 CI 风险的个人，并提供 治疗目标，以改善 PAYAS 的整体生活质量和适应性功能 儿童癌症。