Mutations and target genes in Adenoid Cystic Carcinoma

描述（由申请人提供）：囊性癌（ACC）是唾液腺肿瘤中最常见的形式之一，长期预后不良。ACC的治疗包括复杂的头部和颈部手术，然后进行局部放射治疗，这可能治愈局部疾病，但会使患者毁容并具有显著的发病率。此外，大多数患者最终死于远处转移，因此有必要为ACC患者找到改进的治疗策略。ACC肿瘤通常以复发性易位t（6：9）为特征，其将染色体6 q上的MYB（c-Myb）原癌基因融合到染色体9 p上的NFIB基因，导致新型Myb-NFIB融合癌蛋白的表达。c-Myb蛋白编码调节造血细胞、上皮细胞和神经细胞中的分化和增殖的潜在致癌转录因子，并且Myb-NFIB融合蛋白具有完整的N-末端Myb DNA结合结构域，但改变了与NFIB融合的C-末端结构域。我们实验室的前期研究表明，c-Myb的C-末端结构域控制其对靶基因的选择，因此Myb-NFIB融合蛋白可能调控与正常c-Myb不同的基因组。我们提出了三个具体目标来识别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。我们已经组建了一个研究团队，他们在Myb蛋白生物学，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，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，这些数据集将提供大量信息，并将有助于指导这种毁灭性疾病的新治疗策略的开发。

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.