Variation in Gene Expression in Neurofibromatosis Type 1

1 型神经纤维瘤病基因表达的变异

基本信息

批准号：
7734899
负责人：
Leslie Biesecker
金额：
$ 22.56万
依托单位：
NATIONAL HUMAN GENOME RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/7734899
关键词：
Adult Affect American Appearance Benign Biology Biopsy Clinical Condition Congenital chromosomal disease DNA Data Dental Development Disease Echocardiography Eligibility Determination Evaluation Eye Family Family member Foundations Funding Gene Expression Genes Genetic Glomus Tumor Goals Growth Harvest Height Hereditary Disease Human Genetics Image Individual Institution Internist Investigation Journals Lisch nodules Magnetic Resonance Imaging Malignant - descriptor Malignant Neoplasms Manuscripts Measurement Medical Genetics Methods Modality Molecular Molecular Profiling Mutation NF1 gene National Cancer Institute Natural History Neurofibromatosis 1 Numbers Pain Parents Phenotype Photography Pilot Projects Preparation Proteins Protocols documentation Publishing RNA Rate Recruitment Activity Research Ethics Committees Resected Severities Single Nucleotide Polymorphism Skin Societies Spottings Syndrome Testing Time Training Tumor Burden Variant bench to bedside cell growth college dermal neurofibroma design interest lymphoblastoid cell line neurofibroma programs therapeutic target translational approach tumor

项目摘要

Neurofibromatosis type 1 (NF1) is a common (approximately 100,000 Americans) genetic disorder of dysregulated cell growth. Affected people can develop multiple (tens, hundreds, or thousands) of soft fleshy tumors called neurofibromas. People with NF1 also develop malignant cancers. There are limited therapies and no cures for NF1. At this time it is essentially impossible to predict the severity of the disorder. With few exceptions, neither mutation testing of the involved gene (NF1) nor the severity of other affected family members help in estimating the clinical course of the condition. In this study we study the wide variability in severity seen in families with NF1. In our translational approach in the protocol Variation in Gene Expression in Neurofibromatosis Type 1 we quantitatively evaluate families with NF1 using a variety of methods (physical exam, magnetic resonance imaging (MRI), skin and eye photography, echocardiography, dental evaluation). We plan to correlate differences in these measurements with differences in the expression of genes, as determined by a microarray. The ultimate goal is to identify genes associated with severity. Differences in these genes (such as single nucleotide polymorphisms (SNPs)) may be useful in predicting the severity of the disorder. Gene products associated with severity may also be useful therapeutic targets. Dr. Stewart joined NHGRI at the end of November 2004. The IRB approved our project in April 2005 and recruitment started shortly thereafter. By the end of fiscal 2008, we had phenotyped approximately 100 individuals affected with NF1 and collected DNA from nearly all their parents. As a pilot project, we cultured 25 lymphoblastoid cell lines (LCLs) from this phenotyped group of individuals affected with NF1, harvested RNA and hybridized it to microarrays (expression profiling). We then examined the correlation between a variety of phenotypes (height, number of caf-au-lait spots, tumor burden, etc) and each of the approximately 24,000 genes expressed on the array. We identified a gene whose level appears to influence height in individuals with NF1. We then expanded the investigation and cultured LCLs from approximately 75 individuals with NF1 and approximately 25 controls. We are currently investigating the correlation of expression profiles of these 100 subjects with phenotype data. Our goal is to 1) validate the gene identified in the pilot study as a modifier gene (for height in NF1) and 2) identify other putative modifier genes. We have also developed a collaborative project (using funds from the Bench-to-Bedside program) with Dr. Brigitte Widemann and Dr. Thomas Hornyak of the National Cancer Institute to investigate the growth and biology of neurofibromas. The project, titled Natural history and biology of dermal neurofibromas in neurofibromatosis type 1 was approved by the NHGRI IRB in May 2006. It is designed to investigate the growth rate and rate of appearance of dermal neurofibromas using several imaging modalities. We will also biopsy a dermal neurofibroma and normal skin. To streamline recruiting, the eligibility criteria overlap with that of our primary project, Variation in Gene Expression in Neurofibromatosis Type 1. By the end of fiscal 2008, we were evaluating, longitudinally, the dermal neurofibromas from 12 individuals affected with NF1. Since Dr. Stewart is trained as an internist, he has a special interest in manifestations of NF1 affecting adults. To this end, we have been evaluating individuals with NF1 with unique and under-recognized disease features in the adult. By the end of fiscal 2008 we had resected glomus tumors from four individuals with NF1, which are uncommon but painful benign tumors in the fingertips. We have made significant progress in understanding the molecular mechanism of the development of the tumors and are preparing a manuscript detailing our findings. Another manuscript investigating Lisch nodules in adults with NF1 is also in preparation. In fiscal 2008, we published in the American Journal of Medical Genetics an invited review on the 9q subtelomere deletion syndrome, an uncommon chromosomal disorder Dr. Stewart described as a genetics fellow at another institution. We presented our findings at the 2007 annual meeting of the American Society of Human Genetics, 2008 annual meeting of the American College of Medical Genetics and the 2008 annual meeting of the Childrens Tumor Foundation.

1 型神经纤维瘤病 (NF1) 是一种常见的（大约有 100,000 名美国人）细胞生长失调的遗传性疾病。受影响的人可能会出现多个（数十、数百或数千）软肉质肿瘤，称为神经纤维瘤。患有 NF1 的人也会患上恶性肿瘤。 NF1 的治疗方法有限且无法治愈。目前基本上无法预测疾病的严重程度。除少数例外，相关基因 (NF1) 的突变检测或其他受影响家庭成员的严重程度都无助于估计该病的临床病程。在这项研究中，我们研究了 1 型 NF 家族中严重程度的巨大差异。在我们的 1 型神经纤维瘤病基因表达变异方案的转化方法中，我们使用各种方法（体格检查、磁共振成像 (MRI)、皮肤和眼睛摄影、超声心动图、牙科评估）定量评估 NF1 家族。我们计划将这些测量值的差异与通过微阵列确定的基因表达的差异相关联。最终目标是识别与严重程度相关的基因。这些基因的差异（例如单核苷酸多态性 (SNP)）可能有助于预测疾病的严重程度。与严重程度相关的基因产物也可能是有用的治疗靶点。 Stewart 博士于 2004 年 11 月底加入 NHGRI。IRB 于 2005 年 4 月批准了我们的项目，此后不久就开始招募。到 2008 财年底，我们已经对大约 100 名 NF1 患者进行了表型分析，并收集了几乎所有他们父母的 DNA。作为一个试点项目，我们从受 NF1 影响的表型组个体中培养了 25 个类淋巴母细胞系 (LCL)，收获 RNA 并将其与微阵列杂交（表达谱）。然后，我们检查了各种表型（身高、咖啡斑数量、肿瘤负荷等）与芯片上表达的约 24,000 个基因之间的相关性。我们发现了一种基因，其水平似乎会影响 NF1 个体的身高。然后，我们扩大了调查范围，并从约 75 名 NF1 患者和约 25 名对照者中培养了 LCL。我们目前正在研究这 100 名受试者的表达谱与表型数据的相关性。我们的目标是 1) 验证试点研究中确定的基因作为修饰基因（NF1 中的身高），2) 确定其他假定的修饰基因。我们还与国家癌症研究所的 Brigitte Widemann 博士和 Thomas Hornyak 博士开发了一个合作项目（使用 Bench-to-Bedside 计划的资金）来研究神经纤维瘤的生长和生物学。该项目名为“1 型神经纤维瘤病中真皮神经纤维瘤的自然历史和生物学”，于 2006 年 5 月获得 NHGRI IRB 批准。该项目旨在使用多种成像方式研究真皮神经纤维瘤的生长速率和出现速率。我们还将对真皮神经纤维瘤和正常皮肤进行活检。为了简化招募流程，资格标准与我们的主要项目“1 型神经纤维瘤病基因表达变异”的资格标准重叠。到 2008 财年底，我们对 12 名 NF1 患者的真皮神经纤维瘤进行了纵向评估。由于 Stewart 医生接受过内科医生培训，因此他对影响成人的 NF1 表现特别感兴趣。为此，我们一直在评估具有独特且未被充分认识的成人疾病特征的 NF1 个体。到 2008 财年底，我们已经切除了 4 名 NF1 患者的血管球瘤，这是一种罕见但令人疼痛的指尖良性肿瘤。我们在理解肿瘤发展的分子机制方面取得了重大进展，并正在准备一份详细介绍我们发现的手稿。另一份研究 NF1 成人 Lisch 结节的手稿也在准备中。 2008 财年，我们在《美国医学遗传学杂志》上发表了一篇关于 9q 亚端粒缺失综合征的特邀评论，这是另一家机构的遗传学研究员斯图尔特博士描述的一种罕见的染色体疾病。我们在美国人类遗传学会 2007 年年会、美国医学遗传学会 2008 年年会和儿童肿瘤基金会 2008 年年会上介绍了我们的研究结果。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The chromosome 9q subtelomere deletion syndrome.

9q 染色体亚端粒缺失综合征。

DOI：
发表时间：
2007-11-15
期刊：
影响因子：
0
作者：
Stewart, Douglas R;Kleefstra, Tjitske
通讯作者：
Kleefstra, Tjitske

Cephalometry in adults and children with neurofibromatosis type 1: Implications for the pathogenesis of sphenoid wing dysplasia and the "NF1 facies".

成人和儿童 1 型神经纤维瘤病的头影测量：对蝶骨翼发育不良和“NF1 相”发病机制的影响。

DOI：
发表时间：
2015-11
期刊：
影响因子：
0
作者：
Cung, Winnie;Freedman, Laura A;Khan, Nicholas E;Romberg, Elaine;Gardner, Pamela J;Bassim, Carol W;Baldwin, Andrea M;Widemann, Brigitte C;Stewart, Douglas R
通讯作者：
Stewart, Douglas R

Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1.

有丝分裂重组作为 1 型神经纤维瘤病胃肠道间质瘤替代发病机制的证据。

DOI：
发表时间：
2007-01
期刊：
影响因子：
4
作者：
Stewart, Douglas R;Corless, Christopher L;Rubin, Brian P;Heinrich, Michael C;Messiaen, Ludwine M;Kessler, Lisa J;Zhang, Paul J;Brooks, David G
通讯作者：
Brooks, David G