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.

工作总结：这项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，重点是那些遗传性并与其他内分泌腺体中多个肿瘤和异常相关的疾病（即垂体）。我们的实验室已经研究了Carney Complex（CNC）（也称为粘膜综合体，斑点皮肤色素沉着，内分泌过度运动和Schwannomas）和相关综合症，并且已经确定了两个基因的CNC基因在染色体上的基因2（2p16）和17q222-24）。通过临床研究，对这些患者的更好诊断程序和治疗方法进行了测试。通过遗传连锁分析以及其他分子遗传和细胞遗传学技术，正在研究两个基因组基因座对染色体2和17参与疾病表达的表达。构建了2P16染色体区域的综合遗传和物理图，用于从该区域克隆引起CNC的基因。对原发性肿瘤细胞系（由我们的患者建立）的研究确定了该地图中心的扩增区域。但是，其他肿瘤显示该区域的杂合丧失（LOH）。从17q22-24基因座开始，LOH研究导致将PRKAR1A基因鉴定为疾病病例中约40％的CNC的基因。 Prkar1a是一种新型的肿瘤抑制基因。与NIH的其他实验室合作，正在研究细胞系中PRKAR1A突变的功能后果。最近，正在创建具有突变体Prkar1a的转基因表达的动物模型。与Mayo诊所合作，还发现了与CNC相关综合症患者（即PEUTZ-JEGHERS综合征）患者的遗传缺陷。最近在我们的实验室中还完成了一个鉴定负责遗传性肾上腺皮质醛源醛（家族性高醛型II-FH-II）的基因的基因组筛查，并确定了7p22的FH-II基因座。正在为其他内分泌肿瘤（包括儿童肾上腺皮质癌和垂体肿瘤）的遗传学进行其他工作。