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

基本信息

批准号：
10704496
负责人：
Charis Eng
金额：
$ 48.18万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
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/10704496
关键词：
Accounting Adopted Adoption Adult Affect Biochemical Pathway Biological Biological Factors Biological Markers Biology Breast Cells Child Clinical Code Computer software Copy Number Polymorphism Data Derivation procedure Development Developmental Delay Disorders Diagnosis Disease Disparate Early Intervention Etiology Family General Population Genetic Genome Genomics Genotype Growth High-Risk Cancer Individual Inherited Intervention Knowledge Lead Learning Longitudinal Studies Macrocephaly Malignant Neoplasms Measurable Medical Medicine Mental Health Metabolic Methods Modeling Mutate Mutation Mutation Detection National Institute of Child Health and Human Development Neurodevelopmental Disorder Nomograms Observational epidemiology 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 Tumor Suppressor Genes Untranslated RNA Variant autism spectrum disorder cancer predisposition cancer prevention cancer risk candidate identification clinical practice clinical translation 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 metabolic phenotype metabolome metabolomics model development multimodality phenotypic biomarker point of care polygenic risk score predictive marker predictive modeling prevent prospective risk stratification segregation translational approach whole genome young adult

项目摘要

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.

项目摘要/摘要种系PTEN突变引起PTEN Hamartoma肿瘤综合征（PHTS），遗传过度生长和癌症易感障碍。除了是与癌症相关的经典肿瘤抑制基因之外，PTEN突变是一个神经发育障碍的最常见原因，包括自闭症谱系障碍（ASD）和发育延迟（DD）。但是，尚不清楚哪个特定的PHT个人会发展ASD/DD，重要的是，是否所有患有PHT和ASD/DD的儿童长大后具有与非ASD/DD PHT相同的癌症风险。广泛的章程该建议的目的是系统地表征PHT的个体的修饰景观，以便最终将当前的研究和临床实践范式从人口水平的概率转移到更精确的个体疾病的风险概率。基于当前的知识差距和原则数据，中央假设是种系PTEN变异与其他相关可测量的生物学因素的相互作用，例如种系基因组修饰剂或代谢差异，提供了ASD/DD的更精确的风险估计，可能是在个人级别的PHT中合并症。该假设将通过三个特定目的进行检验：（目标1）在PHTS患者衍生的血浆和淋巴母细胞系中，鉴定ASD/DD的代谢组标志物和癌症风险；（AIM 2）通过多模式表型驱动的基因组表征ASD/DD的基因组标记和PHT中的癌症风险分析包括拷贝数变化分析，基于家庭的全基因组测序和全基因组推导多基因风险评分；（目标3）在PHT中生成ASD/DD和癌症风险的预测模型，包括翻译促进个人患者风险分层的临床采用的方法。这项以患者为中心的研究将依靠现有的均匀表型PHTS队列，并持续具有生殖线PTEN的个人突变。拟议的研究与NICHD的优先事项和机构间自闭症委员会保持一致 ASD的战略计划是（1）了解与ASD相关的遗传综合征与此类疾病有关的医疗和心理健康状况；（2）确定可靠的标记以预测ASD 由于最早的干预措施可改善ASD的结果，因此在PHT中及时。（3）了解自闭症生物学通过研究代谢组和基因组标记，重要的是，整合了这些因素通过预测模型开发。拟议的研究具有创新性，因为除了研究单基因（较少异质）和具有PTEN-ASD/DD的个体的深度/统一表型，该提议进行除了观察性流行病学询问外，还研究了基本的代谢组和基因组因素首先会导致ASD/DD患者的合并症癌症风险改变。结论，在除了发现科学外，还预计该应用程序会导致临床医生可以在护理点。