PQ - 9 As genomic sequencing methods continue to identify large numbers of novel cancer mutations, how can we identify the mutations in a given tumor that are most critical to the maintenance of its oncogenic phenotype? Background: DNA sequencing of cancer genomes has shown that individual tumors often contain many mutations that change protein coding regions, frequently as many as 30 to 150 changes in a single tumor. Many of the individually mutated genes are found in multiple tumors or are found in genes that have been implicated previously as cancer genes. These frequent mutations, often called “driver mutations”, are believed to be important for tumor development. However, sequencing studies have also detected many mutations that are found only rarely. It is not clear if or how these low frequency mutations might contribute to tumor development. This question asks how we can determine which mutations have key roles in tumor development? Feasibility: The recent identification of mutations through genomic sequencing provides a gene list and mutations for study. The challenge of this Provocative Question is to establish methods that will determine which changes are important for tumor development and use these methods to study the roles of these mutations. The task is complicated because of the large number of mutations and because it is not clear when in tumor development the mutation appeared and consequently what selective pressure this mutation may have overcome. Implications of success: Finding out which mutations are important for tumor development will provide an important set of proteins for drug discovery, shed light on the various selective pressures experienced in tumor development, and help us predict what mutations found in ongoing sequencing projects are likely to be important in tumorigenesis. |
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