Molecular Genetics of Adrenocortical Tumors and Related

肾上腺皮质肿瘤及相关肿瘤的分子遗传学

• 批准号: 6432531
• 负责人: Constantine A. Stratakis
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432531
• 关键词: adrenal disorder; artificial chromosomes; cell line; clinical research; endocrine neoplasm; family genetics; genetic disorder; genetic mapping; human genetic material tag; human subject; hyperaldosteronism; nervous system neoplasms; syndrome

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.

工作概述：本工作的目的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、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）（也称为黏液瘤、斑点性皮肤色素沉着、内分泌过度活跃和神经鞘瘤复合体）及相关综合征的家族，并在染色体2 （2p16）和17 （17q22-24）上发现了两个含有CNC基因的位点。通过临床调查，为这些患者提供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，正在研究2号染色体和17号染色体上的两个基因组位点在疾病表达中的作用。构建了2p16染色体区域的全面遗传和物理图谱，从该区域克隆cnc引起基因。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扩增区域。然而，其他肿瘤显示该区域的杂合缺失（LOH）。从17q22-24位点，LOH研究鉴定出PRKAR1A基因在大约40%的疾病病例中是导致CNC的基因。PRKAR1A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PRKAR1A突变的功能后果；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。我们的实验室最近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。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。