Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, United States of America.
Department of Nutrition and Systems Biology and Bioinformatics Program, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States of America.
PLoS Comput Biol. 2024 Oct 2;20(10):e1012449. doi: 10.1371/journal.pcbi.1012449. eCollection 2024 Oct.
Persons with germline variants in the tumor suppressor gene phosphatase and tensin homolog, PTEN, are molecularly diagnosed with PTEN hamartoma tumor syndrome (PHTS). PHTS confers high risks of specific malignancies, and up to 23% of the patients are diagnosed with autism spectrum disorder (ASD) and/or developmental delay (DD). The accurate prediction of these two seemingly disparate phenotypes (cancer vs. ASD/DD) for PHTS at the individual level remains elusive despite the available statistical prevalence of specific phenotypes of the syndrome at the population level. The pleiotropy of the syndrome may, in part, be due to the alterations of the key multi-functions of PTEN. Maintenance of genome integrity is one of the key biological functions of PTEN, but no integrative studies have been conducted to quantify the DNA damage response (DDR) in individuals with PHTS and to relate to phenotypes and genotypes. In this study, we used 43 PHTS patient-derived lymphoblastoid cell lines (LCLs) to investigate the associations between DDR and PTEN genotypes and/or clinical phenotypes ASD/DD vs. cancer. The dynamics of DDR of γ-irradiated LCLs were analyzed using the exponential decay mathematical model to fit temporal changes in γH2AX levels which report the degree of DNA damage. We found that PTEN nonsense variants are associated with less efficient DNA damage repair ability resulting in higher DNA damage levels at 24 hours after irradiation compared to PTEN missense variants. Regarding PHTS phenotypes, LCLs from PHTS individuals with ASD/DD showed faster DNA damage repairing rate than those from patients without ASD/DD or cancer. We also applied the reaction-diffusion partial differential equation (PDE) mathematical model, a cell growth model with a DNA damage term, to accurately describe the DDR process in the LCLs. For each LCL, we can derive parameters of the PDE. Then we averaged the numerical results by PHTS phenotypes. By performing simple subtraction of two subgroup average results, we found that PHTS-ASD/DD is associated with higher live cell density at lower DNA damage level but lower cell density level at higher DNA damage level compared to LCLs from individuals with PHTS-cancer and PHTS-neither.
携带有肿瘤抑制基因磷酸酶及张力蛋白同源物（PTEN）种系变异的个体，分子诊断为 PTEN 错构瘤肿瘤综合征（PHTS）。PHTS 会增加特定恶性肿瘤的风险，高达 23%的患者被诊断为自闭症谱系障碍（ASD）和/或发育迟缓（DD）。尽管人群中综合征的特定表型存在统计学流行率，但仍难以在个体水平上准确预测 PHTS 的这两种看似不同的表型（癌症与 ASD/DD）。这种综合征的多效性可能部分归因于 PTEN 的关键多功能改变。基因组完整性的维持是 PTEN 的关键生物学功能之一，但尚未进行综合研究来量化 PHTS 个体中的 DNA 损伤反应（DDR），并将其与表型和基因型相关联。在这项研究中，我们使用 43 个 PHTS 患者来源的淋巴母细胞系（LCL）来研究 DDR 与 PTEN 基因型和/或临床表型 ASD/DD 与癌症之间的关联。使用指数衰减数学模型分析 γ 辐照 LCL 的 DDR 动力学，以拟合 γH2AX 水平的时间变化，γH2AX 水平报告 DNA 损伤程度。我们发现 PTEN 无意义变异与更有效的 DNA 损伤修复能力相关，导致照射后 24 小时的 DNA 损伤水平更高，而 PTEN 错义变异则相反。关于 PHTS 表型，患有 ASD/DD 的 PHTS 个体的 LCL 显示出比没有 ASD/DD 或癌症的患者更快的 DNA 损伤修复率。我们还应用了反应扩散偏微分方程（PDE）数学模型，该模型是一种带有 DNA 损伤项的细胞生长模型，以准确描述 LCL 中的 DDR 过程。对于每个 LCL，我们可以得出 PDE 的参数。然后，我们根据 PHTS 表型对数值结果进行平均。通过对两个亚组平均结果进行简单减法，我们发现与 LCL 来自 PHTS-癌症和 PHTS-无的个体相比，PHTS-ASD/DD 与较低的 DNA 损伤水平下更高的活细胞密度和更高的 DNA 损伤水平下更低的细胞密度相关。
