Determining the relationship between amplified DNA location and function in cancer

Recent studies identified gene amplification, an increase of up to 100’s of DNA copy numbers of selected genes, as a major driver in multiple cancers leading to poor prognosis. Cancers frequently contain amplifications of oncogenes leading to more aggressive phenotypes, or amplifications of genes that confer therapy resistance. Although the genetic basis of amplifications is being actively studied, our understanding of how the organization of amplified DNA impacts transcriptional output is very limited. This is especially relevant as amplifications can be found either within chromosomes or in extra-chromosomal DNA (ecDNA) elements that appear to change their nuclear localization during the cell cycle. The overarching goal of this proposal is to gain deep molecular understanding of the interplay between amplification organization and transcription. Our lab obtained significant preliminary data showing ecDNA amplifications occupy specific locations at different stages of the cell cycle. We further identified initial evidence for differences in transcriptional output from ecDNA and intrachromosomal amplifications. In our proposed collaborative work, we will combine experimental and computational approaches, to uncover the spatiotemporal dynamics of amplified DNA and resulting transcriptional output in cancer. This will provide groundbreaking insight on how gene regulation of amplified DNA can promote cancer evolution.