Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer.
Functional Impact of Chromatin Remodeling Gene Mutations and Predictive Signature for Therapeutic Response in Bladder Cancer.
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DOI：
10.1158/1541-7786.mcr-17-0260
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发表时间：
2018-01
期刊：
影响因子：
--
通讯作者：
Theodorescu D
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文献类型：
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作者：
Duex JE;Swain KE;Dancik GM;Paucek RD;Owens C;Churchill MEA;Theodorescu D
尿路上皮癌占膀胱癌病例的大多数。使用下一代测序（NGS）技术，我们发现显着百分比（83%）的肿瘤在染色质重塑基因中存在突变。在这里，我们研究了两个染色质重塑基因，EP 300和它的paradox，CREBBP，这是突变的近三分之一的患者突变的功能相关性。有趣的是，几乎一半的错义突变集中在EP 300/CREBBP的组蛋白乙酰转移酶（HAT）结构域。该结构域催化乙酰基转移到靶分子如组蛋白，从而调节染色质动力学。因此，具有EP 300或CREBBP突变的患者可能具有相应蛋白质修饰组蛋白和控制转录谱的能力的改变。事实上，已经确定EP 300（64%）和CREBBP（78%）中的许多错义HAT突变是HAT失活的。这些失活突变也与患者的侵袭性疾病相关。引人注目的是，预测软件Mutation Assessor准确地预测了每个HAT错义突变的功能后果。最后，开发了与HAT活性丧失相关的基因表达特征，并且该特征与四个患者数据集中更具侵袭性的癌症相关。进一步支持该评分准确反映HAT活性的观点，我们发现它对癌细胞对mocetinostat（一种组蛋白脱乙酰酶（HDAC）抑制剂）的治疗有反应。本研究为EP 300和CREBBP的靶向测序以及使用基因谱特征预测患者的治疗反应提供了理论依据。
Urothelial carcinoma accounts for most of the bladder cancer cases. Using next-generation sequencing (NGS) technology, we found that a significant percentage (83%) of tumors had mutations in chromatin-remodeling genes. Here, we examined the functional relevance of mutations in two chromatin-remodeling genes, EP300 and its paralog, CREBBP, which are mutated in almost one-third of patients. Interestingly, almost half of missense mutations cluster in the histone-acetyltransferase (HAT) domain of EP300/CREBBP. This domain catalyzes the transfer of an acetyl group to target molecules such as histones, thereby regulating chromatin dynamics. Thus, patients with EP300 or CREBBP mutations may have alterations in the ability of the corresponding proteins to modify histone proteins and control transcriptional profiles. In fact, it was determined that many of the missense HAT mutations in EP300 (64%) and CREBBP (78%) were HAT-inactivating. These inactivating mutations also correlated with invasive disease in patients. Strikingly, the prediction software Mutation Assessor accurately predicted the functional consequences of each HAT missense mutation. Finally, a gene expression signature was developed that associated with loss of HAT activity and that this signature was associated with more aggressive cancer in four patient datasets. Further supporting the notion that this score accurately reflects HAT activity, we found it is responsive to treatment of cancer cells to mocetinostat, a histone deacetylase (HDAC) inhibitor. This study provides a rationale for targeted sequencing of EP300 and CREBBP and use of a gene profiling signature for predicting therapeutic response in patients.