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.

这项工作的目的是了解导致影响肾上腺皮质的疾病的遗传和分子机制，重点是遗传性并与其他内分泌腺体中多种肿瘤和异常相关的疾病（即垂体）。我们的实验室研究了CARNEY COMPLEX（CNC）和相关综合症的家庭，并确定了CNC的基因基因，包括染色体2（2P16）和17（17q22-24）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参与该疾病的表达。已经构建了2P16染色体区域的综合遗传和物理图。在本培养的原发性肿瘤细胞系中的研究（由我们的患者建立）确定了该地图中心的基因组不稳定性区域。肿瘤研究导致在大约40％的疾病病例中，在17q22-24上鉴定了PRKAR1A基因为负责CNC的基因。 Prkar1a是一种新型的肿瘤抑制基因。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FNCTIONS和激素反应的中心信号通路。与NIH的其他实验室合作，正在研究细胞系中PRKAR1A突变的功能后果。最近，正在创建具有突变体Prkar1a的转基因表达的动物模型。与Mayo诊所合作，还发现了与CNC相关综合症患者（即PEUTZ-JEGHERS综合征）患者的遗传缺陷。在我们的实验室还完成了负责遗传性肾上腺皮质醛源症（家族性高醛型II-FH-II）的基因鉴定基因的基因组筛查，并在7p22上确定了FH-II的基因座。鉴定由家族性paragangliomas，肾上腺，胃基质和肺部肿瘤组成的综合征的基因组宽筛查正在进行中。正在为其他内分泌肿瘤（包括儿童肾上腺皮质癌和垂体肿瘤）的遗传学进行其他工作。最近在肾上腺癌的队列中鉴定出TP53基因的“签名”突变。临床项目包括良性肾上腺皮质肿瘤的功能表征，对内分泌肿瘤学中遗传标记的使用的评估以及成像和其他诊断方法的改善，以鉴定肾上腺和垂体肿瘤。