Cushing's Disease Whole Exome Sequencing Study

库欣病全外显子组测序研究

• 批准号: 10004474
• 负责人: James Mills
• 金额: $ 14.27万
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10004474
• 关键词: Adrenal Glands; Biochemical; Blood Pressure; Blood specimen; Characteristics; Childhood; Chromosomal Instability; Clinical; Clinical Data; Copy Number Polymorphism; Corticotropin; DNA; Data; Data Set; Diabetes Mellitus; Diagnosis; Disease; Documentation; Etiology; Exons; Face; Family member; Fracture; Genetic; Genetic Code; Genome; Genomics; Goals; Growth; Height; Histology; Hormonal; Hydrocortisone; Hypertension; Medical; Methods; Minority; National Institute of Child Health and Human Development; Operative Surgical Procedures; Patients; Phenotype; Pituitary Corticotropin Secreting Adenoma; Pituitary Gland; Pituitary Neoplasms; Pituitary-dependent Cushing' s disease; Play; Population Control; Posterior Pituitary Gland; Proteins; Publishing; Radiation; Recurrence; Reporting; Research; Research Project Grants; Risk; Role; Sampling; Subgroup; Syndrome; Testing; Translating; Tumor Tissue; Variant; adenoma; aged; cancer genome; cavernous sinus; cost; exome; exome sequencing; follow-up; genetic variant; genome-wide; genomic aberrations; glucose tolerance; outcome forecast; pediatric patients; rare variant; response; tool; tumor; whole genome

We are currently analyzing whole exome sequencing (WES) with appropriate follow up to identify important genetic factors associated with Cushing's disease (CD) and related abnormal physical features. The ultimate goal is to identify a genetic variant or variants that cause CD. CD is a condition in which the pituitary gland produces inappropriately high levels of adrenocorticotropic hormone (ACTH). The ACTH stimulates the adrenal gland to produce excess cortisol, leading to clinical disease. CD is caused by ACTH secreting pituitary tumors. CD is a serious condition. It requires surgery to remove the tumor. The tumors sometimes recur in which case radiation or medical therapy is required which is not always successful. CD can cause a wide range of problems due to the high cortisol levels. These include diabetes, fractures, poor growth, and hypertension. CD can be fatal. Whole exome sequencing (WES) is a powerful tool for identifying important genetic variants associated with medical conditions. It is an efficient method of determining the genetic code (sequence) of all the regions in the genome that are translated into protein, the exons. The exons constitute about 1% of DNA, thus sequencing exons provides a large amount of information at a lower cost than sequencing the entire genome. Pediatric aged patients seen at NICHD with a confirmed diagnosis of CD are evaluated for this study. Those who have histopathologically confirmed disease in conjunction with DNA, hormonal documentation of the disease and complete clinical data are potential cases. Analysis comparing variants found in the cases with large control populations has been done. In addition, the data are being examined for copy number variants in the exons to determine if they play a role in Cushing's disease. Whole exome sequencing has now been performed on tumor tissue in patients where tumor tissue is available to determine if there are specific tumor-associated variants in the exome. These data have been analyzed in the same manner as the blood samples. In addition, samples from patients who have ectopic posterior pituitaries have been obtained and whole exome sequenced. The data have been screened using standard data sets to identify rare variants. Since the last report, the group has published on large genomic aberrations in corticotropinomas as a predictor of tumor aggressiveness and prognosis. We studied whether somatic copy number variants (CNVs)in pituitary tumors are related to progression and invasiveness. Chromosomal instability, involving 23% to 59% of the tumor genome, was noted in 5 of the 27 samples (18.5%). The patients with tumors showing chromosomal instability had similar clinical and biochemical characteristics to the remaining patients, except for tumor size, which was larger (median size 18 mm vs 5.5 mm, P = 0.005). Tumors with chromosomal instability were also associated with a higher rate of invasion of the cavernous sinus (P = 0.029). There was insufficient information on persistence or recurrence of CD to determine whether the risk was higher in those with chromosomal instability. In summary a subgroup of corticotropinomas demonstrates chromosomal instability that is associated with markers of aggressiveness of these adenomas. It appears that more genomic gains/losses in a few, rare corticotropinomas may predict poorer prognosis for pediatric patients with CD.

我们目前正在分析具有适当后续的整个外显子组测序（WES），以识别与库欣氏病（CD）和相关异常物理特征相关的重要遗传因素。 最终目标是确定引起CD的遗传变异或变体。 CD是垂体可产生不适当水平的肾上腺皮质激素（ACTH）的条件。 ACTH刺激肾上腺产生多余的皮质醇，导致临床疾病。 CD是由分泌垂体肿瘤的ACTH引起的。 CD是一个严重的状况。 它需要手术以切除肿瘤。 肿瘤有时会复发，在这种情况下，需要辐射或医疗疗法，这并不总是成功的。 由于皮质醇水平较高，CD可能引起广泛的问题。 这些包括糖尿病，骨折，生长不良和高血压。 CD可能是致命的。 整个外显子组测序（WES）是识别与医疗状况相关的重要遗传变异的强大工具。 这是确定基因组中所有区域的遗传密码（序列）的有效方法，这些方法被转化为蛋白质，外显子。 外显子约占DNA的1％，因此，测序外显子比对整个基因组进行测序的成本更低的成本提供了大量信息。 在NICHD上看到的有确认的CD诊断的儿科老年患者进行了本研究的评估。 那些在组织病理学上证实疾病与DNA结合使用的人，疾病的激素文献和完整的临床数据是潜在的病例。 分析比较在控制群体较大的情况下发现的变体。 此外，还在研究外显子中的拷贝数变体的数据，以确定它们是否在Cushing的疾病中起作用。 现在，已经对肿瘤组织的肿瘤组织进行了整个外显子组测序，这些患者有可用的肿瘤组织来确定外显子组中是否存在特定的肿瘤相关变体。这些数据的分析方式与血液样本相同。 此外，已经获得了来自异位后垂体的患者的样品，并进行了整个外显子组测序。 使用标准数据集对数据进行了筛选，以识别稀有变体。 自上次报告以来，该小组已经发表了关于皮质性瘤的大基因组畸变，作为肿瘤侵袭性和预后的预测指标。我们研究了垂体肿瘤中的体拷贝数变体（CNV）是否与进展和侵入性有关。 在27个样品中的5个（18.5％）中有5个染色体不稳定性，涉及肿瘤基因组的23％至59％。表现出染色体不稳定性的肿瘤患者的临床和生化特征与其余患者具有相似的临床和生化特征，但肿瘤大小（中位数较大18毫米vs 5.5 mm，p = 0.005）。具有染色体不稳定性的肿瘤也与海绵窦的浸润率更高有关（p = 0.029）。关于CD的持久性或复发的信息不足以确定染色体不稳定性患者的风险是否更高。 总而言之，一组皮质性瘤的亚组表明染色体不稳定性与这些腺瘤的侵略性标记有关。看来，在少数罕见的皮质可瘤瘤中，基因组收益/损失会预测儿科患者的预后较差。