Flipping the switch: Salk scientists shed new light on genetic changes that turn cancer genes on
New research into cancer-causing gene mutations could lead to better ways to predict and treat disease
LA JOLLA—Cancer, caused by an abnormal proliferation of cells, is the second leading cause of death worldwide. Researchers at the Salk Institute focused on specific mechanisms that activate oncogenes, which are altered genes that can turn normal cells into cancerous cells.
Cancer can be caused by genetic mutations, but the impact of specific types such as structural variants that break and rejoin DNA can vary widely. The findings, published in Nature on December 7, 2022, show that the activity of these mutations depends on the distance between a particular gene and the sequences that regulate the gene, as well as the level of activity of the regulatory sequences involved.
When genetic mutations cause chromosomes to break and fuse in different ways, normal cells can become cancerous. In this image, normal chromosomes (blue) are shown with chromosomes (green and red) that have been modified using CRISPR-Cas9 genome engineering and fused together.Click here for a high resolution image. Credit: Salk Institute
This work is advancing the ability to predict and interpret genetic mutations found in cancer genomes that cause disease.
“If we can better understand why a person has cancer and what particular genetic mutations cause it, we can better assess the risks and pursue new treatments,” says Salk physician-scientist Jesse Dixon, lead author of the paper. and Assistant Professor in the Gene Expression Laboratory.
Most genetic mutations have no impact on cancer and molecular incidents that lead to the activation of an oncogene are relatively rare. Dixon’s lab studies how genomes are organized in 3D space and seeks to understand why these changes occur in some circumstances, but not in the majority. The team also wants to identify factors that might distinguish where and when these events occur.
“A gene is like a light and what regulates it is like the switches,” Dixon explains. “We find that due to structural variants in cancer genomes, many switches can potentially turn on ‘a particular gene’.
Using CRISPR-Cas9 gene editing, the research team introduced genetic mutations by cutting DNA at certain locations in the genome. They found that some of the variants they created had major impacts on neighboring gene expression and could ultimately cause cancer, but most had virtually no impact. Some genes seemed to go haywire when introduced into environments with new regulatory sequences, and others were unaffected at all. The type of sequence introduced seemed to have a huge impact on whether the cell became cancerous or not.
Credit: Salk Institute
“Our next step is to test whether there are other factors in the genome that contribute to oncogene activation,” says Zhichao Xu, postdoctoral fellow at Salk and co-first author of the paper. “We are also excited about a new CRISPR genome editing technology that we are developing to make this type of genome engineering work much more efficient.”
Other study authors are Sahaana Chandran, Victoria T. Le, Rosalind Bump, Jean Yasis, Sofia Dallarda, Samantha Marcotte, Benjamin Clock, Nicholas Haghani, Chae Yun Cho, Selene Tyndale, Graham McVicker, and Geoffrey M. Wahl of Salk ; Dong-Sung Lee of Seoul University, South Korea; and Kadir Akdemir and P. Andrew Futreal of the University of Texas MD Anderson Cancer Center.
The research was supported by the National Institutes of Health (DP5OD023071), the Leona M. and Harry B. Helmsley Charitable Trust (2017-PG-MED001), the National Institutes of Health National Cancer Institute (R35 CA197687) and the Breast Cancer Research Foundation.
DO I: 10.1038/s41586-022-05504-4
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