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

项目概要/摘要 生殖系PTEN突变导致PTEN错构瘤肿瘤综合征（PHTS），一种遗传性过度生长和癌症 易感性障碍除了作为与癌症相关的经典肿瘤抑制基因之外，PTEN突变也是一种 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，目前尚不清楚哪些特定的PHTS个体会发展ASD/DD，重要的是，是否所有的PHTS个体都会发展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。广泛的过度 本提案的目的是系统地评估PHTS患者的修饰符景观， 最终将当前的研究和临床实践范式从人群水平的概率转向更精确的 个体水平的疾病风险概率。根据目前的知识差距和原理证明数据， 假设是生殖系PTEN变异与其他相关可测量生物学因素，如 生殖系基因组修饰或代谢差异，提供更精确的ASD/DD风险估计， PHTS中的共病癌症在个体水平上。将通过三个具体目标来检验这一假设：（目标1） 鉴定PHTS患者来源血浆和淋巴母细胞系中ASD/DD和癌症风险的代谢组学标志物; (Aim 2）通过多模式表型驱动的基因组学方法来表征PHTS中ASD/DD和癌症风险的基因组标志物。 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推导 （目的3）建立一个预测ASD/DD和PHTS中癌症风险的模型，包括翻译 促进个体患者风险分层的临床采用的方法。这项以病人为中心的研究将依赖于一个 现有的统一表型PHTS队列和携带生殖系PTEN的个体的持续前瞻性增加 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 ASD的战略计划，优先事项是（1）了解与ASD相关的遗传综合征及其并发症， 与这些疾病相关的医学和心理健康状况;（2）确定可靠的标记物来预测ASD 在PHTS中及时，因为最早的干预导致ASD的结果改善;（3）了解 通过研究代谢组学和基因组标记，重要的是，整合这些因素， 通过预测模型的发展。这项研究是创新的，因为除了研究单基因 (less异质性）和深/均匀表型组的个人与PTEN-ASD/DD，该建议去 除了观察流行病学调查之外，还调查了潜在的代谢组学和基因组学因素， 首先导致ASD/DD改变，然后导致ASD/DD个体的共病癌症风险。在结束时， 除了发现科学，这项应用预计将导致临床医生可以在 即时护理

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.