TopNet Helps Identify Non-Mutated Genes Crucial to Cancer

Wilmot Cancer Institute researchers are a step closer to understanding the complex gene interactions that cause a cell to become malignant. In a new study, published in Cell Reports today, the group used network modeling to hone in on a set of such interactions that are critical to malignancy.

“Targeting non-mutated proteins that are essential to making cells cancerous is a broader approach that could be used in multiple cancers,” said lead researcher Hartmut Land, “but it’s hard to find these non-mutated, essential genes.” The team developed a new network modeling method, called TopNet, that they paired with genetic experiments in cells and mice to pinpoint functionally relevant gene networks.

Land’s group previously identified a very diverse set of non-mutated genes that are crucial to cancer. In this study, the group wanted to see how those genes interact—starting with a subset of 20 genes. Increasing or decreasing the expression of one gene in cultured cells would have numerous effects on the expression levels of the other genes in the set.

After weeding out models that didn’t closely fit the observed data and further focusing on gene interactions that appeared in at least 80 percent of the models, the team was left with a manageable set of 24 high-confidence gene interactions. Subsequent experiments demonstrated that these interactions often play an important role in malignancy. The group has already tested a sampling of the genetic interactions revealed by TopNet, and confirmed via experiments in cells and mice that the interactions are functionally linked. Next, the group intends to test the limits of TopNet, with the intent to use this method to find potential cancer therapies that are broadly effective.