Molecular Genetics Of Adrenocortical Tumors And Related

肾上腺皮质肿瘤及相关肿瘤的分子遗传学

• 批准号: 6664171
• 负责人: Constantine A. Stratakis
• 金额: --
• 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/6664171
• 关键词: adrenal disorder; adrenal neoplasm; artificial chromosomes; biological signal transduction; cell line; family genetics; genetic mapping; human genetic material tag; human subject; hyperaldosteronism; neoplasm /cancer genetics; nervous system neoplasms; patient oriented research

The goal of this work is to understand the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are hereditary and associated with multiple tumors and abnormalities in other endocrine glands (i.e. the pituitary gland). Our laboratory has studied families with Carney complex (CNC)and related syndromes and has identified loci harboring genes for CNC, including regions on chromosomes 2 (2p16) and 17 (17q22-24). Through genetic linkage analysis and other molecular techniques, the participation of various genomic loci in the expression of the disease is being investigated. A comprehensive genetic and physical map of the 2p16 chromosomal region has been constructed. Studies in cultured primary tumor cell lines (established from our patients) identified a region of genomic instability in the center of this map. Tumor studies led to the identification of the PRKAR1A gene on 17q22-24 as the gene responsible for CNC in approximately 40% of the cases of the disease. PRKAR1A is a novel tumor suppressor gene; it is also the main regulatory subunit of protein kinase A, a central signaling pathway for many of the cellular fnctions and hormonal responses. In collaboration with other laboratories at the NIH, the functional consequences of PRKAR1A mutations are being investigated in cell lines; more recently, animal models with transgenic expression of mutant PRKAR1A are being created. In collaboration with Mayo Clinic, the genetic defects in patients with CNC-related syndromes (i.e., Peutz-Jeghers syndrome) are also being identified. A genome-wide screen for the identification of gene(s) responsible for inherited adrenocortical aldosteronomas (familial hyperaldosteronism type II - FH-II) was also completed in our laboratory, identifying a locus for FH-II on 7p22. A genome wide screen for the identification of a syndrome composed of familial paragangliomas, adrenal, gastric stromal and pulmonary tumors is ongoing. Additional work is being done collaboratively on the genetics of other endocrine tumors, including childhood adrenocortical cancer and pituitary tumors. Most recently a "signature" mutation of the TP53 gene was identified in a cohort of adrenal cancers. Clinical projects include the functional characterization of benign adrenocortical tumors, the evaluation of the use of genetic markers in endocrine oncology, and the improvement of imaging and other diagnostic approaches for the identification of adrenal and pituitary tumors.

这项工作的目标是了解导致影响肾上腺皮质疾病的遗传和分子机制，重点关注那些遗传性的、与多种肿瘤和其他内分泌腺（即垂体）异常相关的疾病。我们的实验室研究了患有卡尼综合症 (CNC) 和相关综合征的家庭，并确定了携带 CNC 基因的位点，包括 2 号染色体 (2p16) 和 17 号染色体 (17q22-24) 上的区域。通过遗传连锁分析和其他分子技术，正在研究各种基因组基因座在疾病表达中的参与。 2p16 染色体区域的综合遗传和物理图谱已经构建。对培养的原代肿瘤细胞系（从我们的患者建立）的研究确定了该图谱中心的基因组不稳定区域。肿瘤研究发现 17q22-24 上的 PRKAR1A 基因是导致大约 40% 的 CNC 病例的基因。 PRKAR1A是一种新型抑癌基因；它也是蛋白激酶 A 的主要调节亚基，蛋白激酶 A 是许多细胞功能和激素反应的中心信号传导途径。与 NIH 的其他实验室合作，正在细胞系中研究 PRKAR1A 突变的功能后果；最近，人们正在创建具有突变体 PRKAR1A 转基因表达的动物模型。与 Mayo Clinic 合作，还确定了 CNC 相关综合征（即 Peutz-Jeghers 综合征）患者的遗传缺陷。我们的实验室还完成了全基因组筛选，以鉴定负责遗传性肾上腺皮质醛固酮瘤（II 型家族性醛固酮增多症 - FH-II）的基因，确定了 7p22 上的 FH-II 基因座。正在进行全基因组筛查，以鉴定由家族性副神经节瘤、肾上腺、胃间质和肺部肿瘤组成的综合征。正在就其他内分泌肿瘤（包括儿童肾上腺皮质癌和垂体肿瘤）的遗传学进行更多合作。最近，在一组肾上腺癌中发现了 TP53 基因的“特征”突变。临床项目包括良性肾上腺皮质肿瘤的功能表征、内分泌肿瘤学中遗传标记的使用评估，以及用于识别肾上腺和垂体肿瘤的成像和其他诊断方法的改进。