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：
9982678
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9982678
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 Expression Profiling 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 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 outcome forecast overexpression programs promoter rare cancer screening therapeutic development therapeutic target transcription factor transcriptome transcriptome sequencing tumor tumorigenesis validation studies

项目摘要

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.

项目概要/摘要腺样囊性癌 (ACC) 是小唾液腺和大唾液腺中第二常见的恶性肿瘤腺体，长期预后较差。 ACC 肿瘤的分子研究变得复杂化肿瘤的相对稀有性、诊断和特征的差异以及缺乏真正的 ACC 细胞线。大多数 ACC 肿瘤含有反复出现的 t(6;9) 易位，该易位融合了 MYB 原型 6q 染色体上的癌基因与 9p 染色体上的 NFIB 基因相比。易位有多种影响：导致 c-Myb 转录因子的截短、致癌形式的表达，并将 MYB 基因紧邻组织特异性增强子，导致 ACC 肿瘤中过度表达。主要挑战在研究 ACC 肿瘤时，需要对罕见肿瘤进行详细的分子表征足够旧的样本可以提供临床结果信息。为了应对这一挑战，我们开发了并优化了创新的 RNA-seq 方法来分析来自档案甲醛固定的 RNA，石蜡包埋 (FFPE) ACC 肿瘤样本，使我们能够进行深入的转录组分析在这些罕见的肿瘤样本上。我们的努力导致了涉及 MYB 和 MYB 的新型、反复融合的鉴定以及相关的 MYBL1 癌基因，编码 A-Myb 转录因子。我们发现了新的见解研究 ACC 肿瘤中这些基因的激活机制并表征基因表达 ACC 肿瘤的概况以及它们与 MYB 和 MYBL1 癌基因表达的关系。这些发现表明我们处于独特的地位来研究导致 ACC 肿瘤的机制并确定重要的因素 ACC 肿瘤的调节因子和潜在治疗靶点。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 癌基因引起的，这些基因由于受组织特异性增强子，导致诱导特征性的 ACC 特异性基因表达程序。在此修订后的续展申请中，我们将以我们已完成的研究为基础，并利用我们为 ACC 肿瘤样本生成了广泛的 RNA-seq 数据。我们将专注于表演对 RNA-seq 数据进行广泛而深入的生物信息学分析并进行分子验证深入了解导致 ACC 肿瘤的机制。我们还将研究其机制导致 ACC 肿瘤中 MYB 和 MYBL1 癌基因过度表达，目的是识别新的治疗目标。我们组建了一支由具有分子专业知识的研究人员组成的互动团队生物学、基因组学、生物信息学、生物统计学和计算方法，他们将专注于这些目标回答有关这些毁灭性肿瘤的生物学的关键问题。