Mutations and Target Genes in Adenoid Cystic Carcinoma

项目概要/摘要 腺样囊性癌（ACC）是第二个最常见的恶性肿瘤的小和大涎腺 腺体，长期预后差。ACC肿瘤的分子研究已经被复杂化， 肿瘤相对罕见，诊断和特征的差异，以及缺乏真正的ACC细胞 线绝大多数ACC肿瘤含有复发性t（6; 9）易位，其融合MYB原蛋白， 染色体6q上的NFIB基因与染色体9p上的NFIB基因。易位有多种影响： 导致c-Myb转录因子的截短的致癌形式的表达，并使其与 MYB基因与组织特异性增强子相邻，导致ACC肿瘤中的过表达。的主要挑战 在研究ACC肿瘤时，需要对罕见肿瘤进行详细的分子表征 样本的年龄足以获得临床结果信息。为了应对这一挑战，我们开发了 并优化了创新的RNA-seq方法，以分析来自档案甲醛固定的RNA， 石蜡包埋（FFPE）ACC肿瘤样本，这使我们能够进行深入的转录组分析 这些罕见的肿瘤样本。我们的努力导致了新的，复发性融合涉及MYB的鉴定， 以及编码A-Myb转录因子的相关MYBL 1癌基因。我们发现了新的见解 这些基因在ACC肿瘤中的激活机制，并表征了基因表达 ACC肿瘤的特征以及它们如何与MYB和MYBL 1癌基因表达相关。这些发现使 我们在研究导致ACC肿瘤的机制和确定重要的 ACC肿瘤的潜在治疗靶点。我们的研究结果使我们假设唾液 腺ACC肿瘤是由突变的MYB或MYBL 1癌基因过度表达引起的，这是由于 组织特异性增强子，导致诱导特征性ACC特异性基因表达程序。 在修订后的续期申请中，我们将在已完成的研究的基础上， 我们已经为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 以深入了解导致ACC肿瘤的机制。我们还将研究 导致ACC肿瘤中MYB和MYBL 1癌基因的过度表达，目的是鉴定新的 治疗目标我们已经组建了一个互动的调查小组，他们具有分子生物学方面的专业知识， 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， 回答关于这些毁灭性肿瘤的生物学的关键问题。

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.