Mutations and Target Genes in Adenoid Cystic Carcinoma

腺样囊性癌的突变和靶基因

• 批准号: 10657124
• 负责人: SCOTT A. NESS
• 金额: $ 44.54万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-10 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657124
• 关键词: Adenoid Cystic Carcinoma; Bioinformatics; Biological Markers; Biology; Breast; C-terminal; Cell Line; Cell model; Cells; Characteristics; Chimeric Proteins; Chromosomes; Clinic; Clinical; Data; Denmark; Development; Distant Metastasis; Enhancers; Epigenetic Process; Event; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Genomics; Glean; Goals; Growth; Heterogeneity; Human; Institution; Laboratories; Lacrimal gland structure; Lead; Learning; Length; MYB gene; MYBL1 gene; Methods; Molecular; Molecular Biology; Morbidity - disease rate; Morphology; Mus; Mutation; N-terminal; NFIB gene; Oncogenic; Oncoproteins; Operative Surgical Procedures; Paper; Patients; Positioning Attribute; Prognosis; Proteins; Publishing; Radiation; Reconstructive Surgical Procedures; Recurrence; Relapse; Research; Role; Salivary Gland Adenoid Cystic Carcinoma; Salivary Gland Neoplasms; Salivary Glands; Sampling; Shapes; Skin; Subgroup; Testing; Tissues; Training; Translating; Validation; Work; biomarker development; cohort; driver mutation; follow-up; high risk; migration; novel therapeutic intervention; overexpression; patient derived xenograft model; patient prognosis; patient subsets; promoter; relapse risk; sample archive; transcription factor; transcriptome sequencing; tumor; usability

Project Summary/Abstract Adenoid Cystic Carcinoma (ACC) is the second most common type of salivary gland tumor, but can also arise in other tissues such as lacrimal gland, breast and skin. ACC tumors display heterogeneous morphology and have a variable clinical course. Many ACC patients survive 10 years or more after the standard therapy of surgery and radiation, but a fraction succumb much more quickly and others acquire distant metastases or relapse 5 or more years after the initial treatment. So patients often have to endure significant morbidity including reconstructive surgery while living under the threat of recurrence for decades. ACC is one of the only human tumors in which mutations involving the MYB oncogene are known to be the most common driver. A large fraction of ACC tumors harbor a t(6;9) translocation, which juxtaposes an enhancer from the NFIB gene on chromosome 9p close to the MYB oncogene on chromosome 6q. However, ACC tumors have heterogeneous molecular characteristics. About half the tumors that express MYB harbor translocations that fuse the MYB and NFIB genes, resulting in a ‘broken’ or truncated MYB gene that can only express Myb proteins with C-terminal truncations – mutations that are known to activate the oncogenic potential of the Myb transcription factor. But the remaining MYB positive tumors appear to express full-length Myb proteins without any fusion to NFIB. And some tumors harbor different translocations that position the MYB gene close to other enhancers or that involve the related MYBL1 gene instead of MYB. This molecular heterogeneity is also reflected in the subgroups of ACC patients that have been identified by gene expression profiling, including at least one poor-prognosis subgroup with a unique gene expression profile and another subgroup that expresses neither MYB nor MYBL1 and must harbor as yet unidentified driver mutations. Deciphering the molecular events that lead to ACC has been complicated by the lack of adequate cell models for this tumor. To avoid any issues from highly selected or mislabeled cell lines, our strategy has been to utilize primary salivary gland ACC patient samples, an approach that has led to numerous important results that have reshaped our understanding of ACC tumors. In this competing renewal application we will generate the largest set of ACC tumor RNA-seq data in order to move the field forward in several ways. We will address the heterogeneity of ACC tumors and patients, set the stage for the development of new therapeutic strategies that target Myb proteins, use patient samples in a translational way to validate experimental results about Myb protein biology and we will begin migrating our approaches to clinical (CLIA) laboratories to make them usable in the clinic.

项目摘要/摘要 腺样囊性癌(ACC)是第二常见的涎腺肿瘤类型，但也可以 出现在其他组织中，如泪腺、乳房和皮肤。ACC肿瘤形态不均一 并有不同的临床病程。许多ACC患者在接受标准治疗后存活10年或更长时间 手术和放射治疗，但一小部分人死得更快，另一些人则获得远处转移或 初次治疗后5年或更长时间复发。因此，患者往往不得不忍受严重的发病率 包括重建手术，同时生活在复发的威胁下数十年。 ACC是仅有的几种涉及myb癌基因突变的人类肿瘤之一 最常见的司机。很大一部分ACC肿瘤存在t(6；9)易位，这种易位并列于 染色体9p上NFIB基因的增强子与6q上的myb癌基因相近。然而， ACC肿瘤具有异质性的分子特征。大约一半表达MYB的肿瘤是由 融合MYB和NFIB基因的易位，导致MYB基因“断裂”或截断 表达带有C末端截断的Myb蛋白-已知可激活致癌基因的突变 Myb转录因子的潜力。但剩下的MYB阳性肿瘤似乎表达全长 未与NFIB融合的MYB蛋白。一些肿瘤有不同的易位，使 MYB基因与其他增强子接近或涉及相关的MYBL1基因而不是MYB。这种分子 异质性也反映在通过基因表达确定的ACC患者亚组中 包括至少一个具有独特基因表达谱的预后不良亚组和另一个亚组 既不表达MYB也不表达MYBL1的亚群，且必须存在尚未识别的驱动突变。 由于缺乏足够的细胞，破译导致ACC的分子事件变得复杂 这种肿瘤的模型。为了避免因高度选择或错误标记的细胞系而产生的任何问题，我们的策略是 利用原发唾液腺ACC患者样本，这一方法已导致许多重要结果 这重塑了我们对ACC肿瘤的理解。在这一竞争性续订申请中，我们将生成 最大的一组ACC肿瘤RNA-SEQ数据，以便在几个方面推动该领域的发展。我们将解决 ACC肿瘤和患者的异质性，为开发新的治疗策略奠定了基础 以Myb蛋白为靶点，以翻译的方式使用患者样本来验证关于Myb的实验结果 蛋白质生物学，我们将开始将我们的方法移植到临床(CLIA)实验室，使其可用 在诊所里。