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.

我们目前正在分析全外显子组测序 (WES) 并进行适当的随访，以确定与库欣病 (CD) 和相关异常身体特征相关的重要遗传因素。 最终目标是识别导致 CD 的遗传变异。 CD 是垂体产生不适当的高水平促肾上腺皮质激素 (ACTH) 的疾病。 ACTH 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的垂体肿瘤引起的。 CD 是一种严重的疾病。 需要手术切除肿瘤。 肿瘤有时会复发，在这种情况下需要放射或药物治疗，但这并不总是成功。 由于皮质醇水平较高，CD 会引起多种问题。 这些包括糖尿病、骨折、生长不良和高血压。 CD 可能是致命的。 全外显子组测序 (WES) 是识别与医疗状况相关的重要遗传变异的强大工具。 它是一种确定基因组中所有翻译成蛋白质（外显子）区域的遗传密码（序列）的有效方法。 外显子约占 DNA 的 1%，因此外显子测序可以比对整个基因组进行测序以更低的成本提供大量信息。 本研究对在 NICHD 就诊并确诊为 CD 的老年儿童患者进行评估。 那些经组织病理学结合 DNA、疾病激素记录和完整临床数据证实患有疾病的人是潜在病例。 已经对病例中发现的变异与大量对照人群进行了比较分析。 此外，正在检查数据中外显子的拷贝数变异，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全外显子组测序，以确定外显子组中是否存在特定的肿瘤相关变异。这些数据的分析方式与血液样本相同。 此外，还获得了异位垂体后叶患者的样本并进行了全外显子组测序。 数据已使用标准数据集进行筛选，以识别罕见变异。 自上次报告以来，该小组发表了关于促肾上腺皮质激素瘤的大基因组畸变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）是否与进展和侵袭性相关。 27 个样本中的 5 个（18.5%）发现染色体不稳定性，涉及肿瘤基因组的 23% 至 59%。肿瘤显示染色体不稳定的患者与其余患者具有相似的临床和生化特征，只是肿瘤尺寸较大（中位尺寸18毫米与5.5毫米，P = 0.005）。染色体不稳定的肿瘤也与较高的海绵窦侵袭率相关（P = 0.029）。关于 CD 持续或复发的信息不足，无法确定染色体不稳定的患者的风险是否更高。 总之，促肾上腺皮质激素瘤亚组表现出与这些腺瘤侵袭性标志物相关的染色体不稳定性。一些罕见的促肾上腺皮质激素瘤中更多的基因组增益/丢失可能预示着 CD 儿科患者的预后较差。