Characterization of recurrent cancer mutations that cause misregulated translation

 描述(由申请人提供)：癌症突变可以通过导致蛋白质水平的错误调节而产生深远的后果。例如，增加端粒酶基因表达的转录调控突变影响到约70%的黑色素瘤患者，在其他几种癌症中也很常见。虽然最近的研究已经开始揭开遗传变异和RNA水平之间的联系，但蛋白质水平与RNA表达的相关性往往很差。翻译效率被认为是造成这种差异的一大部分原因。然而，目前对人类翻译效率的遗传决定因素及其与癌症的相关性知之甚少。令人兴奋的初步数据表明，人类基因变异可以调节翻译，重要的是，~18%的膀胱癌患者被发现存在非编码突变，这种突变会损害可能的Rab GTPase激活剂的翻译。目前这项提议的中心假设是，导致错误调控翻译的基因突变在癌症中具有重要的功能。这项拟议的研究是朝着我的目标迈出的合乎逻辑的下一步，我的目标是成为一名独立资助的研究人员，并拥有一个积极的研究计划，以确定遗传学在控制癌症基因表达中的作用。虽然我在统计学、计算生物学和基因组学方面有广泛的培训和经验，但我对癌症研究还是个新手。因此，我在这里的总体目标是在获得癌症生物学方面的额外培训的同时 表征导致错误翻译的复发癌症突变。为了实现我的目标，我将充分利用斯坦福大学优越的培训环境。预期的结果包括对影响18%膀胱癌患者的以前未被识别的突变的功能表征，以及开发新的分析和实验方法，以查明癌症中基因表达失调的一个严重缺失的维度。这项拟议的研究将使我能够将我在人类遗传学和计算生物学方面的培训应用于一个重要的问题，同时接受更多的癌症生物学培训，推动我走向独立。这些结果将对增进我们对癌症中翻译调控的遗传学基础的理解产生重大的积极影响。

 DESCRIPTION (provided by applicant): Cancer mutations can have profound consequences by causing misregulation of protein levels. For example, transcriptional regulatory mutations that increase telomerase gene expression affect ~70% of all melanoma patients and are frequent in several other cancers. While recent studies have begun to unravel the connection between genetic variation and RNA levels, protein levels often correlate poorly with RNA expression. Translation efficiency has been suggested to account for a large fraction of this discrepancy. However, little is currently known about genetic determinants of translation efficiency in humans, and their relevance to cancer. Exciting preliminary data suggests that human genetic variants can regulate translation, and importantly ~18% of all bladder cancer patients are found to harbor noncoding mutations that impair translation of a putative Rab GTPase activator. The central hypothesis of the current proposal is that genetic mutations that cause misregulated translation are functionally important in cancer. The proposed study is the logical next step towards my goal of becoming an independently funded investigator with an active research program to identify the role of genetics in controlling gene expression in cancer. While I have extensive training and experience in statistics, computational biology and genomics, I am new to cancer research. Hence, my overall objective here is to obtain additional training in cancer biology while characterizing recur- rent cancer mutations that lead to misregulated translation. To achieve my objective, I will take full ad- vantage of the excellent training environment at Stanford Universit. The expected outcomes include the functional characterization of previously unrecognized mutations affecting 18% of bladder cancer patients, and development of novel analytical and experimental methods that will pinpoint a critically missing dimension of gene expression misregulation in cancer. The proposed study will enable me to apply my training in human genetics and computational biology to an important problem while receiving additional training in cancer biology propelling me to independence. These results will have a major positive impact by enhancing our understanding of the genetic basis of translation regulation in cancer.