Modeling Autism and Comorbid Cancer Risk in Individuals with Germline PTEN Mutations

种系 PTEN 突变个体的自闭症和共病癌症风险建模

• 批准号: 10358435
• 负责人: Charis Eng
• 金额: $ 43.62万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-14 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358435
• 关键词: Accounting; Adopted; Adoption; Adult; Affect; Biochemical Pathway; Biological; Biological Factors; Biology; Breast; Cells; Child; Clinical; Code; Computer software; Copy Number Polymorphism; Data; Derivation procedure; Development; Developmental Delay Disorders; Diagnosis; Disease; Early Intervention; Epidemiology; Etiology; Family; General Population; Genetic; Genome; Genomics; Genotype; High-Risk Cancer; Individual; Inherited; Intervention; Knowledge; Lead; Longitudinal Studies; Macrocephaly; Malignant Neoplasms; Measurable; Medical; Medicine; Mental Health; Metabolic; Methods; Modeling; Mutate; Mutation; National Institute of Child Health and Human Development; Neurodevelopmental Disorder; Nomograms; Outcome; PTEN Hamartoma Tumor Syndrome; PTEN autism spectrum disorder; PTEN gene; Patients; Persons; Phenotype; Plasma; Population; Prevalence; Prevention; Probability; Public Health; Reaction; Research; Risk; Risk Estimate; Risk Management; Sampling; Science; Series; Strategic Planning; Syndrome; System; Testing; Therapeutic; Thyroid Gland; Time; Tumor Suppressor Genes; Untranslated RNA; Variant; autism spectrum disorder; base; cancer predisposition; cancer prevention; cancer risk; clinical practice; clinically translatable; cohort; comorbidity; disorder risk; enzyme pathway; evidence base; genome sequencing; genome-wide; genomic biomarker; high risk; improved outcome; individual patient; individuals with autism spectrum disorder; innovation; lifetime risk; lymphoblastoid cell line; machine learning model; metabolic phenotype; metabolome; metabolomics; model development; multimodality; phenotypic biomarker; point of care; polygenic risk score; predictive marker; predictive modeling; prevent; preventive intervention; prospective; risk stratification; segregation; statistical and machine learning; translational approach; whole genome; young adult

PROJECT SUMMARY/ABSTRACT Germline PTEN mutations cause PTEN hamartoma tumor syndrome (PHTS), a hereditary overgrowth and cancer predisposition disorder. Besides being a classical tumor suppressor gene associated with cancer, PTEN mutations are one of the most common causes of neurodevelopmental disorders, including autism spectrum disorder (ASD) and developmental delay (DD). However, it is not known which specific PHTS individual will develop ASD/DD, and importantly, whether all children with PHTS and ASD/DD grow up to have identical cancer risks as non-ASD/DD PHTS. The broad over-arching objective of this proposal is to systematically characterise the modifier landscape of individuals with PHTS in order to ultimately shift current research and clinical practice paradigms from population-level probabilities towards more precise individual-level disease risk probabilities. Based on the current knowledge gaps and proof-of-principle data, the central hypothesis is that interactions of germline PTEN variation with other pertinent measurable biological factors, such as germline genomic modifiers or metabolic differences, provide more precise risk estimates of ASD/DD and possibly, comorbid cancer in PHTS at the individual level. This hypothesis will be tested through three specific aims: (Aim 1) To identify metabolomic markers of ASD/DD and cancer risk in PHTS patient-derived plasma and lymphoblastoid cell lines; (Aim 2) To characterize genomic markers of ASD/DD and cancer risk in PHTS via multimodal phenotype-driven genomic analyses including copy number variation analysis, family-based whole-genome sequencing, and genome-wide derivation of polygenic risk scores; (Aim 3) To generate a predictive model of ASD/DD and cancer risk in PHTS including translational methods to facilitate clinical adoption for individual patient risk stratification. This patient-focused research will rely on an existing uniformly phenotyped PHTS cohort and continuing prospective accrual of individuals harboring germline PTEN mutations. The proposed research aligns with the NICHD Priorities and the Interagency Autism Coordinating Committee strategic plan for ASD in that the priority is (1) to understand genetic syndromes associated with ASD and the co-occurring medical and mental health conditions associated with such disorders; (2) to identify reliable markers to predict for ASD within PHTS in a timely manner, since earliest interventions lead to improved outcomes in ASD; (3) to understand the biology of autism through investigating metabolomic and genomic markers and importantly, integrating these factors through predictive model development. The proposed research is innovative because in addition to studying a monogenic (less heterogeneous) and deeply/uniformly phenotyped group of individuals with PTEN-ASD/DD, this proposal goes beyond observational epidemiological interrogation into investigating underlying metabolomic and genomic factors that contribute first to altered ASD/DD and then comorbid cancer risks in individuals with ASD/DD. Upon conclusion, in addition to discovery science, this application is projected to result in predictive methods that clinicians can adopt at the point-of-care.

项目概要/摘要 种系 PTEN 突变导致 PTEN 错构瘤综合征 (PHTS)，这是一种遗传性过度生长和癌症 易感障碍。 PTEN 突变除了是与癌症相关的经典肿瘤抑制基因外，也是其中之一 神经发育障碍的最常见原因，包括自闭症谱系障碍 (ASD) 和发育障碍 延迟（DD）。然而，尚不清楚哪个特定的 PHTS 个体会患上 ASD/DD，重要的是，是否所有的 PHTS 个体都会患上 ASD/DD 患有 PHTS 和 ASD/DD 的儿童长大后患癌症的风险与非 ASD/DD PHTS 相同。广泛的总体 该提案的目的是系统地描述 PHTS 患者的修饰景观，以便 最终将当前的研究和临床实践范式从群体水平的概率转向更精确的概率 个体水平的疾病风险概率。根据当前的知识差距和原理验证数据，中央 假设是种系 PTEN 变异与其他相关的可测量生物因素的相互作用，例如 种系基因组修饰剂或代谢差异，提供更精确的 ASD/DD 风险评估，并可能， PHTS 中个体水平的共病癌症。该假设将通过三个具体目标进行检验：（目标 1） 鉴定 PHTS 患者血浆和淋巴母细胞系中 ASD/DD 的代谢组学标志物和癌症风险； （目标 2）通过多模式表型驱动的基因组来表征 ASD/DD 的基因组标记和 PHTS 中的癌症风险 分析包括拷贝数变异分析、基于家族的全基因组测序和全基因组衍生 多基因风险评分； （目标 3）生成 ASD/DD 和 PHTS 癌症风险的预测模型，包括转化模型 促进临床采用个体患者风险分层的方法。这项以患者为中心的研究将依赖于 现有统一表型 PHTS 队列和持续前瞻性累积携带种系 PTEN 的个体 突变。拟议的研究符合 NICHD 优先事项和机构间自闭症协调委员会 自闭症谱系障碍 (ASD) 战略计划的重点是 (1) 了解与自闭症谱系障碍相关的遗传综合征以及同时发生的疾病 与此类疾病相关的医疗和精神健康状况； (2) 确定可靠的标记物来预测 ASD 及时在 PHTS 范围内进行干预，因为最早的干预措施可以改善 ASD 的结果； （3）了解 通过研究代谢组学和基因组标记来研究自闭症生物学，重要的是，整合这些因素 通过预测模型的开发。拟议的研究具有创新性，因为除了研究单基因 （较少异质性）和深度/均匀表型的 PTEN-ASD/DD 个体群体，该提案认为 除了观察流行病学调查之外，还研究潜在的代谢组学和基因组因素 首先导致 ASD/DD 患者发生改变，然后导致 ASD/DD 患者共病癌症风险。综上所述，在 除了发现科学之外，该应用预计将产生临床医生可以在现场采用的预测方法 护理点。