Mutations and target genes in Adenoid Cystic Carcinoma

腺样囊性癌的突变和靶基因

基本信息

批准号：
8899757
负责人：
SCOTT A. NESS
金额：
$ 16.34万
依托单位：
UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8899757
关键词：
Address Adenoid Cystic Carcinoma Alternative Splicing Bioinformatics Biological Assay Biology Biometry Breast C-terminal Carcinoma Chimeric Proteins Chromosomal translocation Chromosomes Computing Methodologies DNA Binding Domain Data Set Development Disease Distant Distant Metastasis Epigenetic Process Epithelial Epithelial Cells Gene Expression Gene Targeting Genes Genomics Goals Head and Neck Surgery Hematopoietic Laboratories Lead Life Link MYB gene Major salivary gland structure Malignant Neoplasms Maps Methods Minor Molecular Morbidity - disease rate Mutate Mutation N-terminal NFIB gene Neurons Normal Cell Oncogene Proteins Oncogenic Pathway interactions Patients Play Point Mutation Proteins Proto-Oncogene Proteins c-myb Radiation Reagent Recurrence Regulation Regulator Genes Regulatory Pathway Research Personnel Role Salivary Gland Neoplasms Salivary Glands Signal Pathway Signaling Molecule Specificity Structure Technology Tumor Suppressor Genes Variant Work combinatorial functional group genetic regulatory protein human NFIB protein improved innovation insight leukemia neoplastic cell next generation sequencing novel novel therapeutics outcome forecast promoter public health relevance research study success transcription factor treatment strategy tumor

项目摘要

DESCRIPTION (provided by applicant): Cystic Carcinoma (ACC) is one of the most common forms of salivary gland tumors and has a poor long-term prognosis. Therapy for ACC involves complicated head and neck surgery followed by local radiation treatments, which may cure the local disease but leaves patients disfigured and with significant morbidity. In addition, most patients eventually succumb from distant metastases, so finding improved treatment strategies for ACC patients is a necessity. ACC tumors are frequently characterized by a recurrent translocation t(6:9), which fuses the MYB (c-Myb) proto-oncogene on chromosome 6q to the NFIB gene on chromosome 9p, resulting in the expression of novel Myb-NFIB fusion oncoproteins. The c-Myb protein encodes a potentially oncogenic transcription factor that regulates differentiation and proliferation in hematopoietic, epithelial and neural cells, and the Myb-NFIB fusion proteins have intact N-terminal Myb DNA binding domains but altered C-terminal domains fused to NFIB. Previous studies in our laboratory showed that the C-terminal domains of c-Myb control its selection of target genes, so the Myb-NFIB fusion proteins are likely to regulate different sets of genes than normal c-Myb. We propose three specific aims to identify the Myb-NFIB target genes in ACC tumors and to determine how and why they are targeted by the Myb-NFIB fusion oncoprotein. We have assembled a team of investigators with expertise in Myb protein biology, genomics, next-generation sequencing technologies, biostatistics, bioinformatics and computational methods to insure the success of this project. The experiments we propose will provide fundamental information about the causes of ACC tumors and they will produce important epigenetic and gene expression data sets that will be highly informative and that will help guide the development of novel therapeutic strategies for this devastating disease.

描述（由申请人提供）：囊性癌（ACC）是唾液腺肿瘤最常见的形式之一，长期预后较差。 ACC 的治疗涉及复杂的头颈部手术，然后进行局部放射治疗，这可能会治愈局部疾病，但会导致患者毁容并导致严重的发病率。此外，大多数患者最终死于远处转移，因此有必要为 ACC 患者寻找改进的治疗策略。 ACC 肿瘤通常以反复易位 t(6:9) 为特征，该易位将 6q 染色体上的 MYB (c-Myb) 原癌基因与 9p 染色体上的 NFIB 基因融合，导致新型 Myb-NFIB 融合癌蛋白的表达。 c-Myb 蛋白编码一种潜在的致癌转录因子，可调节造血细胞、上皮细胞和神经细胞的分化和增殖，Myb-NFIB 融合蛋白具有完整的 N 端 Myb DNA 结合域，但改变了与 NFIB 融合的 C 端域。我们实验室之前的研究表明，c-Myb 的 C 端结构域控制其对靶基因的选择，因此 Myb-NFIB 融合蛋白很可能调控与正常 c-Myb 不同的基因组。我们提出了三个具体目标，以确定 ACC 肿瘤中的 Myb-NFIB 靶基因，并确定 Myb-NFIB 融合癌蛋白如何以及为何靶向它们。我们组建了一支在 Myb 蛋白质生物学、基因组学、下一代测序技术、生物统计学、生物信息学和计算方法方面具有专业知识的研究人员团队，以确保该项目的成功。我们提出的实验将提供有关 ACC 肿瘤病因的基本信息，并将产生重要的表观遗传和基因表达数据集，这些数据集信息丰富，有助于指导针对这种破坏性疾病的新治疗策略的开发。