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.
Our ability to catalogue mutations across a wide range of cancers have accelerated at an unprecedented speed. A key challenge is to characterize the functional impact of these mutations. The proposed study will develop novel analytical and experimental methods that will lead to comprehensive characterization of functional cancer mutations that cause misregulated translation.
