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.

我们目前正在分析整个外显子组测序(WES)，并进行适当的随访，以确定与库欣病(CD)相关的重要遗传因素和相关的异常身体特征。最终目标是确定导致CD的一个或多个遗传变异。 慢性萎缩性脑病是一种脑下垂体产生不适当的高水平促肾上腺皮质激素(ACTH)的情况。促肾上腺皮质激素刺激肾上腺产生过量的皮质醇，导致临床疾病。CD是由分泌ACTH的脑垂体瘤引起的。CD是一种严重的疾病。它需要手术来移除肿瘤。肿瘤有时会复发，在这种情况下，需要放射治疗或药物治疗，但并不总是有效。由于皮质醇水平较高，镉可引起广泛的问题。这些疾病包括糖尿病、骨折、生长不良和高血压。CD可能是致命的。 全外显子组测序(WES)是识别与疾病相关的重要遗传变异的有力工具。这是一种有效的方法来确定基因组中所有被翻译成蛋白质的区域的遗传密码(序列)，即外显子。外显子约占DNA的1%，因此测序外显子提供了大量的信息，成本低于测序整个基因组。 这项研究对NICHD确诊为CD的老年儿童患者进行了评估。那些有组织病理学证实的疾病并伴有DNA、疾病的激素记录和完整的临床数据的人是潜在的病例。 对在大量对照人群中发现的变异进行了分析比较。此外，正在对这些数据进行外显子拷贝数变异的检查，以确定它们是否在库欣病中发挥作用。 现在已经对有肿瘤组织的患者的肿瘤组织进行了完整的外显子组测序，以确定外显子组中是否有特定的肿瘤相关变异。这些数据的分析方式与血样相同。 此外，还获得了异位后脑垂体症患者的样本，并对其进行了完整的外显子组测序。这些数据已经使用标准数据集进行了筛选，以识别罕见的变异。 自从上一份报告以来，该小组已经发表了关于促肾上腺皮质激素瘤的大基因组异常作为肿瘤侵袭性和预后的预测因子的文章。我们研究了垂体肿瘤中的体细胞拷贝数变异(CNV)是否与疾病进展和侵袭性有关。 27个样本中有5个样本(18.5%)发现染色体不稳定，涉及23%至59%的肿瘤基因组。染色体不稳定性患者的临床和生化特征与其他患者相似，但肿瘤体积较大(中位数为18 mm比5.5 mm，P=0.005)。染色体不稳定的肿瘤也与海绵窦侵袭率高相关(P=0.029)。关于CD的持续性或复发，没有足够的信息来确定染色体不稳定的人是否有更高的风险。 总而言之，促肾上腺皮质激素瘤的一个亚群表现出染色体的不稳定性，这与这些腺瘤侵袭性的标志有关。少数罕见的促肾上腺皮质激素瘤的基因组获得/丢失更多可能预示着儿童CD患者预后较差。