Mutations and Target Genes in Adenoid Cystic Carcinoma

腺样囊性癌的突变和靶基因

• 批准号: 10217096
• 负责人: SCOTT A. NESS
• 金额: $ 35.98万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217096
• 关键词: Address; Adenoid Cystic Carcinoma; Alternative Splicing; Archives; Bioinformatics; Biological Assay; Biological Markers; Biology; Biostatistical Methods; Breast; C-terminal; Cell Line; Characteristics; Chromosomes; Clinical; Computing Methodologies; DNA Binding Domain; Data; Development; Diagnosis; Distant; Enhancers; Formaldehyde; Future; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genomics; Goals; Head and Neck Surgery; Heterogeneity; Human; Lead; MYB gene; MYBL1 gene; Major salivary gland structure; Malignant Neoplasms; Methods; Minor; Molecular; Molecular Analysis; Molecular Biology; Morbidity - disease rate; Mutate; Mutation; N-terminal; NFIB gene; Neoplasm Metastasis; Oncogenes; Oncogenic; Outcome; Paraffin Embedding; Pathway interactions; Patients; Positioning Attribute; Process; Production; Prognosis; Prostate; Proteins; Proto-Oncogenes; RNA; RNA Editing; RNA analysis; Radiation therapy; Recurrence; Regulation; Reporter Genes; Research Personnel; Resources; Salivary Gland Adenoid Cystic Carcinoma; Salivary Glands; Sampling; Specificity; Testing; Tissues; Transcriptional Activation; Validation; Variant; Work; high risk; innovation; insight; leukemia; new therapeutic target; novel; overexpression; programs; promoter; rare cancer; screening; therapeutic development; therapeutic target; transcription factor; transcriptome; transcriptome sequencing; tumor; tumorigenesis; validation studies

Project Summary/Abstract Adenoid Cystic Carcinoma (ACC) is the second most frequent malignancy of the minor and major salivary glands and has poor long-term prognosis. Molecular studies of ACC tumors have been complicated by the relative rarity of the tumors, differences in diagnosis and characterization, and the lack of bona fide ACC cell lines. A large majority of ACC tumors contain a recurrent t(6;9) translocation which fuses the MYB proto- oncogene on chromosome 6q to the NFIB gene on chromosome 9p. The translocations have multiple effects: leading to the expression of truncated, oncogenic forms of the c-Myb transcription factor and juxtaposing the MYB gene next to tissue specific enhancers that lead to overexpression in ACC tumors. The major challenge in studying ACC tumors has been the need to perform detailed molecular characterizations on rare tumor samples that are old enough to have clinical outcome information. To address that challenge, we developed and optimized innovative RNA-seq methods to analyze RNA derived from archival Formaldehyde-Fixed, Paraffin-Embedded (FFPE) ACC tumor samples, which allowed us to perform in-depth transcriptome analyses on these rare tumor samples. Our efforts led to the identification of novel, recurrent fusions involving both MYB and the related MYBL1 oncogene, which encodes the A-Myb transcription factor. We uncovered new insights into the mechanisms of activation of these genes in ACC tumors and characterized the gene expression profiles of ACC tumors and how they are related to MYB and MYBL1 oncogene expression. These findings put us in a unique position to investigate the mechanisms leading to ACC tumors and to identify the important regulators and potential therapeutic targets in ACC tumors. Our results lead us to hypothesize that salivary gland ACC tumors are caused by mutated MYB or MYBL1 oncogenes overexpressed due to regulation by tissue-specific enhancers, resulting in the induction of a characteristic, ACC-specific gene expression program. In this revised renewal application, we will build on the studies that we have completed and make use of the extensive RNA-seq data that we have generated for ACC tumor samples. We will focus on performing extensive and in-depth bioinformatics analyses of the RNA-seq data and on performing molecular validations to gain insights into the mechanisms that lead to ACC tumors. We will also investigate the mechanisms that lead to overexpression of the MYB and MYBL1 oncogenes in ACC tumors, with the goal of identifying new therapeutic targets. We have assembled an interactive team of investigators with expertise in molecular biology, genomics, bioinformatics, biostatistics and computational methods who will focus on these aims to answer key questions about the biology of these devastating tumors.

项目摘要/摘要 腺样囊性癌（ACC）是未成年人和主要唾液的第二常见恶性肿瘤 腺体的长期预后不良。 ACC肿瘤的分子研究使 肿瘤的相对稀有性，诊断和表征的差异以及缺乏真正的ACC细胞 线。绝大多数ACC肿瘤都包含复发性t（6; 9）易位，该易位融合了myb proto- 染色体上的癌基因染色体9p染色体上的NFIB基因。易位具有多种影响： 导致C-MYB转录因子的截短的致癌形式的表达，并并置 MYB基因旁边是组织特异性增强子，导致ACC肿瘤过表达。主要挑战 在研究ACC肿瘤时，需要对稀有肿瘤进行详细的分子特征 足够大的样本具有临床结果信息。为了应对这一挑战，我们发展了 并优化了创新的RNA-seq方法，以分析源自存档甲醛固定的RNA， 石蜡包裹（FFPE）ACC肿瘤样品，这使我们能够进行深入的转录组分析 在这些罕见的肿瘤样品上。我们的努力导致识别涉及MYB的新颖，经常性融合 以及相关的MYBL1癌基因，该癌基因编码A-MYB转录因子。我们发现了新的见解 在ACC肿瘤中这些基因激活的机制，并表征了基因表达 ACC肿瘤的特征以及它们与MyB和MyBl1癌基因表达的关系。这些发现提出 我们处于独特的位置，以研究导致ACC肿瘤的机制并确定重要的 ACC肿瘤中的调节剂和潜在的治疗靶标。我们的结果使我们假设唾液 腺体ACC肿瘤是由突变的Myb或MyBl1致癌基因引起的，因为 组织特异性增强子，导致诱导特征性的ACC特异性基因表达程序。 在此修订后的续订应用中，我们将基于已完成的研究并利用 我们为ACC肿瘤样品生成的广泛RNA-seq数据。我们将专注于表演 RNA-seq数据和进行分子验证的广泛而深入的生物信息学分析 了解导致ACC肿瘤的机制。我们还将调查机制 导致ACC肿瘤中MYB和MYBL1癌基因过度表达，目的是识别新的 治疗靶标。我们组建了一个具有分子专业知识的研究人员的互动团队 生物学，基因组学，生物信息学，生物统计学和计算方法将重点介绍这些目的 回答有关这些毁灭性肿瘤的生物学的关键问题。