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，重点是那些遗传性的和与其他内分泌腺(即脑下垂体)的多发性肿瘤和异常相关的疾病。本实验室对Carney复合体(CnC)及其相关综合征家系进行了研究，并在2号染色体(2p16)和17号染色体(17q22-24)上发现了两个含有CnC基因的基因座。通过遗传连锁分析和其他分子技术，正在调查2号和17号染色体上的两个基因组座位在疾病表达中的参与。构建了2p16染色体区域的遗传和物理图谱，为克隆致病基因奠定了基础。对培养的原代肿瘤细胞系(从我们的患者建立)的研究发现，在这张图的中心有一个基因组不稳定的区域。肿瘤研究证实17q22-24上的PRKAR1A基因在大约40%的疾病病例中是导致慢性肾小球疾病的基因。PRKAR1A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，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，正在研究PRKAR1A突变在细胞系中的功能后果；最近，正在建立转基因表达突变PRKAR1A的动物模型。在与梅奥诊所的合作下，数控相关综合征(即Peutz-Jeghers综合征)患者的基因缺陷也正在确定中。本实验室还完成了遗传性肾上腺皮质醛固酮增多症(家族性醛固酮增多症II-FH-II)基因(S)的全基因组筛查，确定了FH-II在7p22上的一个位点。目前正在进行全基因组筛查，以确定由家族性副神经节瘤、肾上腺、胃间质和肺肿瘤组成的综合征。其他内分泌肿瘤的遗传学方面的其他工作也在合作中进行，包括儿童肾上腺皮质癌和脑垂体瘤。临床项目包括良性肾上腺皮质肿瘤的功能特征和对遗传标记在内分泌肿瘤学中的使用进行评估。

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 two loci harboring genes for CNC on chromosomes 2 (2p16) and 17 (17q22-24). Through genetic linkage analysis and other molecular techniques, the participation of the two genomic loci on chromosomes 2 and 17 in the expression of the disease is being investigated. A comprehensive genetic and physical map of the 2p16 chromosomal region was constructed for the cloning of the CNC-causing gene. 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 ingoing. Additional work is being done collaboratively on the genetics of other endocrine tumors, including childhood adrenocortical cancer and pituitary tumors. Clinical projects include the functional characterization of benign adrenocortical tumors and the evaluation of the use of genetic markers in endocrine oncology.