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有助于认知结果的强大因素 髓母细胞瘤（MB）脑肿瘤的儿科，青少年和年轻成人幸存者（PAYA） 位于小脑。小儿脑肿瘤幸存者的认知风险增加 损害（CI），相对于那些人，健康和残疾的可能性很大 没有癌症病史，而与不必经历救生的幸存者相对 神经毒性化学放疗治疗。但是，认知结果的个体差异 在MB的Payas中，即使最有可能的临床贡献者， 是相同的（即治疗年龄，化学放疗的风险水平，MB肿瘤亚型）。这导致了我们 团队检查遗传素质和其他贡献者，这些临床可能解释了广泛的范围 结果，从轻度到重度CI。除遗传学外，还需要填补重要空白 迄今为止的研究以确定确定的临床风险因素和环境资源 那些有CI风险最大的人。这个位于GA，AL，AL，AL，AL，AL， OH将检查多因素的环境资源（例如，邻里社会经济 逆境，物质困难，护理能力和学校质量），临床因素（例如，年龄 在治疗中，化学放疗的风险水平，MB肿瘤类型）和个体遗传核对（即 候选单核苷酸多态性变体（SNP）。首先，在AIM 1中，研究将检查 三个领域中的每个领域都使用最先进的方法和创新分析 确定CI的最佳预测指标。在其他人群中，多基因风险评分（PR）具有 与单独单独的SNP相比，提供了更强的结果预测。因此，在遗传中 透明域，我们将检查靶向的SNP和相邻的交互式突变以创建 使用机器学习工具来调节RNA表达的强大PRS 与CI相关，并结合了表观遗传学，转录和 蛋白质。其次，在AIM 2中，我们将使用最敏感的 在三个领域的CI预测因素（即临床风险，环境资源和遗传 素质）。这种经验得出的风险算法将通过识别 适应风险的化学放疗治疗和预防性干预措施的条件，以防止， 减轻和管理CI。与2018年《星际法案》和《精密医学》一致 这些发现，这些发现将允许尽早确定有CI风险的人并提供 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。