Focusing on the Common Genetic Links in Cancer Development
In a groundbreaking study published in Cell Reports, researchers from the Wilmot Cancer Institute have made significant strides in understanding the complex gene interactions that cause a cell to become malignant. The study, led by Hartmut 'Hucky' Land, Ph.D., the deputy director of the Wilmot Cancer Institute and the Robert and Dorothy Markin Professor of Biomedical Genetics at the University of Rochester Medical Center, and Matthew McCall, Ph.D., MHS, a Wilmot Cancer Institute investigator and associate professor of Biostatistics and Computational Biology at the University of Rochester Medical Center, focuses on identifying a set of critical gene interactions that are likely to be common across many cancers and could be targets for broad cancer therapies.
The work was completed as part of a $6.3M National Cancer Institute Outstanding Investigator Award granted to Land in 2015, and a K99/R00 grant from the National Human Genome Research Institute was also awarded to McCall for this research.
The researchers used a novel network modeling method, called TopNet, developed by McCall, to identify high-confidence gene interactions relevant for broad cancer therapies. This method considered a number of possible gene network models many times greater than the estimated number of atoms in the universe. After weeding out models that didn't closely fit the observed data and 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.
These downstream genes and their intricate interactions may be common across many cancers and could offer a significant advancement in cancer therapy. Discrete genetic mutations that can be targeted by drugs have only been identified for a small fraction of cancer types, but these mutations rely on a downstream network of non-mutated genes to cause cancer.
Land's group identified a diverse set of non-mutated genes crucial to cancer, and in this study, they focused on understanding their interactions, starting with a subset of 20 genes. 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. Subsequent experiments demonstrated that these interactions often play an important role in malignancy.
The goal of Land's research is to target non-mutated proteins that are essential to making cells cancerous, as this approach could be used in multiple cancers but is challenging to find. The goal of the group is to test the limits of TopNet, with the intent to use this method to find potential cancer therapies that are broadly effective.
Helene McMurray, Ph.D., assistant professor of Biomedical Genetics and Pathology and Laboratory Medicine at the University of Rochester Medical Center, was the first author of the study. The study uses network modeling to identify a set of critical gene interactions that are likely to be common across many cancers and could be targets for broad cancer therapies. This research represents a significant step forward in the fight against cancer, offering new avenues for potential treatments and therapies.
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