Mutations and Target Genes in Adenoid Cystic Carcinoma

项目总结/摘要 腺样囊性癌（ACC）是第二种最常见的涎腺肿瘤，但也可以 出现在其他组织，如泪腺，乳房和皮肤。ACC肿瘤表现出不均匀的形态 并且具有可变的临床过程。许多ACC患者在标准治疗后存活10年或更长时间。 手术和放射治疗，但一小部分死亡更快，其他人获得远处转移， 首次治疗后5年或更长时间复发。所以病人经常要忍受 包括重建手术，几十年来一直生活在复发的威胁下。 ACC是唯一一种已知MYB癌基因突变是导致ACC发生的人类肿瘤。 最常见的司机大部分ACC肿瘤具有t（6; 9）易位，其与ACC肿瘤并列。 来自染色体9p上的NFIB基因的增强子靠近染色体6q上的MYB癌基因。然而，在这方面， ACC肿瘤具有异质性分子特征。大约一半表达MYB的肿瘤 融合MYB和NFIB基因的易位，导致“断裂”或截短的MYB基因， 表达具有C-末端截短的Myb蛋白-已知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 不与NFIB融合的Myb蛋白。一些肿瘤具有不同的易位， MYB基因与其他增强子接近或涉及相关MYBL 1基因而不是MYB。这种分子 异质性也反映在通过基因表达鉴定的ACC患者亚组中 分析，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 一个既不表达MYB也不表达MYBL 1的亚组，并且必须具有尚未鉴定的驱动突变。 由于缺乏足够的细胞，导致ACC的分子事件变得复杂。 这个肿瘤的模型。为了避免高度选择或错误标记的细胞系的任何问题，我们的策略是 利用原发性唾液腺ACC患者样本，这种方法已经导致了许多重要的结果， 重塑了我们对ACC肿瘤的认识在此竞争性更新应用程序中，我们将生成 最大的ACC肿瘤RNA-seq数据集，以便以多种方式推动该领域的发展。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， 我们将开始将我们的方法转移到临床（CLIA）实验室，使其可用 在诊所里

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.