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，重点是那些遗传的、与多发性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卡尼复合体（CNC）和相关综合征的家族，并确定了含有CNC基因的位点，包括染色体2 （2p16）和17 （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位点在疾病表达中的参与情况。一个全面的遗传和物理图谱的2p16染色体区域已经建成。在培养的原代肿瘤细胞系（从我们的患者中建立）的研究中，在该图谱的中心发现了一个基因组不稳定区域。肿瘤研究发现，在大约40%的疾病病例中，17q22-24上的PRKAR1A基因是导致CNC的基因。PRKAR1A是一种新的肿瘤抑制基因；它也是蛋白激酶A的主要调控亚基，而蛋白激酶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，PRKAR1A突变的功能后果正在细胞系中进行研究；最近，正在创建具有突变PRKAR1A转基因表达的动物模型。在与梅奥诊所的合作下，cnc相关综合征（即Peutz-Jeghers综合征）患者的遗传缺陷也正在被确定。我们的实验室也完成了对遗传性肾上腺皮质醛固酮瘤（家族性醛固酮增多症II型- FH-II）基因的全基因组筛选，确定了FH-II在7p22上的一个位点。基因组宽筛选鉴定的综合征组成的家族副神经节瘤，肾上腺，胃间质和肺肿瘤正在进行中。在其他内分泌肿瘤的遗传学方面，包括儿童肾上腺皮质癌和垂体瘤，双方正在进行其他合作工作。最近，在一组肾上腺癌患者中发现了TP53基因的“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，评估遗传标记在内分泌肿瘤学中的应用，以及改进肾上腺和垂体肿瘤的影像学和其他诊断方法。

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.