Aggressive brain cancers are among the most devastating of malignancies diagnosed today. Basic science researchers have shown that during the complex process of brain cancer development, there are many steps. These include the potential activation of mobile DNA sequences in our cells, though no one has had a means of studying these DNAs previously. Appropriate DNA function is at the heart of how a cell works and alterations in DNA (mutations) accompany cancer development. We propose that mobile DNA sequences known as transposons are activated in brain cancer and then in turn mutate other DNA sequences. In this way, mobile DNAs may contribute to the beginning of brain cancer development or the continued growth of disease after effective early therapy. We have developed a new technology (transposon insertion site profiling by deep sequencing or TIP-seq) that allows us to locate the most active mobile DNAs in human cells. We propose to apply TIP-seq to profile mobile DNAs genome-wide in 100 different pathologic samples from glioblastoma multiforme tumors. This should demonstrate whether mobile DNAs are unstable in human brain cancers and if they cause mutations that promote cancer biology. The project would be among the very first to address roles of mobile DNAs in human cancers, and will potentially open our eyes to mechanisms at work in many cancer types.
Much of our DNA is derived from self-propagating sequences termed transposons or mobile DNAs. Technical impediments have severely curtailed our ability to study these sequences in human cancers, though my laboratory has made an advance that now opens this possibility. Focusing on brain cancers, the proposed effort should add a new dimension to our view of human cancer genetics, ultimately impacting how we understand and treat these diseases.
|Rodi?, Nemanja; Sharma, Reema; Sharma, Rajni et al. (2014) Long interspersed element-1 protein expression is a hallmark of many human cancers. Am J Pathol 184:1280-6|