Genome instability, chromosomal structural aberrations, and copy number variation are hallmarks of cancer. Recent advances in sequencing technology have uncovered a large amount of intra-tumoral heterogeneity in both gene expression and chromosomal copy number across a range of tumors. These aberrations are often thought of as integrated and inherited genetic events within tumors. However, new analyses are beginning to demonstrate that some copy number heterogeneity may not be stably inherited. We identified the first enzyme capable of modulating site-specific copy gains and established that the localized chromatin states impact the propensity of a region to undergo rereplication and copy gain. This work established a role for epigenetic regulators and chromatin states in regulating copy number heterogeneity. Furthermore, we established that physiological signals such as hypoxia promote site-specific copy gains of drug-resistant oncogenes, which can contribute to drug resistance. This new perspective on cancer genetics helps explain copy number heterogeneity in tumors and has important clinical implications for characterizing and treating drug-resistant cancer.
My laboratory is expanding on these findings to: