Molecular Genetics Of Adrenocortical Tumors And Related

这项工作的目标是了解导致影响肾上腺皮质的疾病的遗传和分子机制，重点是那些遗传性和与其他内分泌腺（即脑垂体）中的多种肿瘤和异常相关的疾病。我们的实验室研究了Carney综合征（CNC）和相关综合征的家庭，并确定了携带CNC基因的位点，包括染色体2（2 p16）和17（17 q22 -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位点参与疾病的表达。已经构建了2 p16染色体区域的综合遗传和物理图谱。对培养的原发性肿瘤细胞系（从我们的患者中建立）的研究在该图的中心确定了基因组不稳定区域。肿瘤研究导致17 q22 -24上的PRKAR 1A基因被鉴定为在大约40%的疾病病例中负责CNC的基因。PRKAR 1A是一种新的肿瘤抑制基因，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通路。与NIH的其他实验室合作，正在细胞系中研究PRKAR 1A突变的功能后果;最近，正在创建突变PRKAR 1A转基因表达的动物模型。在与马约诊所的合作中，患有CNC相关综合征的患者的遗传缺陷（即，Peutz-Jeghers综合征）也被确定。在我们的实验室中还完成了用于鉴定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）基因的全基因组筛选，在7 p22上鉴定了FH-II的基因座。一个全基因组筛选鉴定的综合征组成的家族性副神经节瘤，肾上腺，胃间质瘤和肺肿瘤正在进行中。其他的工作正在合作进行其他内分泌肿瘤的遗传学，包括儿童肾上腺皮质癌和垂体瘤。最近，在一组肾上腺癌患者中发现了TP 53基因的一个“标志性”突变。临床项目包括良性肾上腺皮质肿瘤的功能特征，评估内分泌肿瘤学中遗传标记的使用，以及改进用于识别肾上腺和垂体肿瘤的成像和其他诊断方法。

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.