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，重点是那些遗传性的和与其他内分泌腺(即脑下垂体)的多发性肿瘤和异常有关的疾病。本实验室研究了Carney复合体(CnC)(也称为粘液瘤、斑点状皮肤色素沉着、内分泌过度活动和神经鞘瘤的复合体)及其相关综合征，并在染色体2(2p16)和17(17q22-24)上发现了两个含有CnC基因的基因座。通过临床调查，对这些患者进行了更好的诊断程序和治疗手段的测试。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座位在疾病表达中的参与。构建了一个完整的2p16染色体区域的遗传和物理图谱，用于从该区域克隆致病基因。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扩增区域。然而，其他肿瘤表现出该区域的杂合性缺失(LOH)。从17q22-24基因座，杂合性缺失研究导致PRKAR1A基因被鉴定为在大约40%的疾病病例中负责计算机控制的基因。PRKAR1A是一种新的肿瘤抑制基因；与美国国立卫生研究院的其他实验室合作，正在细胞系中研究PRKAR1A突变的功能后果；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。本实验室最近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上的一个座位。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。

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.