Molecular Genetics of Adrenocortical Tumors and Related

工作总结：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复合体（CNC）（也称为粘液瘤，斑点状皮肤色素沉着，内分泌过度活跃和神经鞘瘤的复合体）和相关综合征的家庭，并在染色体2（2 p16）和17（17 q22 -24）上确定了两个携带CNC基因的位点。通过临床调查，为这些患者测试更好的诊断程序和治疗手段。通过遗传连锁分析和其他分子遗传学和细胞遗传学技术，正在调查2号和17号染色体上的两个基因组位点参与疾病的表达。构建了2 p16染色体区域的综合遗传和物理图谱，用于从该区域克隆引起CNC的基因。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扩增区域。然而，其他肿瘤显示该区域的杂合性丢失（洛）。从17 q22 -24位点，洛研究导致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;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。我们实验室最近还完成了一项全基因组筛选，以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）的基因，并在7 p22上鉴定了FH-II的基因座。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。

Summary of Work: 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) (also known as the complex of myxomas, spotty skin pigmentation, endocrine overactivity and schwannomas) and related syndromes and has identified two loci harboring genes for CNC on chromosomes 2 (2p16) and 17 (17q22-24). Through clinical investigations, better diagnostic procedures and treatment means for these patients are tested. Through genetic linkage analysis and other molecular genetic and cytogenetic 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 from that area. Studies in cultured primary tumor cell lines (established from our patients) identified a region of amplification in the center of this map. However, other tumors show loss-of-heterozygosity (LOH) of that region. From the 17q22-24 locus, LOH studies led to the identification of the PRKAR1A gene as the gene responsible for CNC in approximately 40% of the cases of the disease. PRKAR1A is a novel tumor suppressor gene; 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 recently completed in our laboratory, identifying a locus for FH-II on 7p22. Additional work is being done collaboratively on the genetics of other endocrine tumors, including childhood adrenocortical cancer and pituitary tumors.