Epigenetics and Genetics
At the Intersection of Epigenetics and Genetics
Dr. Srinivasan Yegnasubramanian
Cancer genetic and epigenetic research has advanced dramatically in the last decade. With leading experts in both disciplines at the Johns Hopkins Kimmel Cancer Center, investigators have uncovered a convergence of the two fields.
Many of the genes mutated in cancer regulate epigenetic processes. This provides a link between genetic mutations and epigenetic abnormalities. Like a volume control, this process can amplify or dampen a series of genes, changing the global expression pattern and dramatically altering the behavior of cells.
“It’s inter-related,” says Dr. Srinivasan Yegnasubramanian, who runs the Kimmel Cancer Center Next Generation Gene Sequencing laboratory. “Many epigenetic problems may have their basis in genetic abnormalities. The genes that get mutated in cancer are often genes that control DNA packaging.”
A prime example of a genetic mutation having epigenetic consequences is the brain cancer gene IDH1, identified by Ludwig Center cancer genetics researcher Nickolas Papdapolous and team in 2008.
IDH1 produces an enzyme that regulates cell metabolism, but a mutation in the gene results in increased production of a metabolite that can affect DNA methylation. IDH1 mutations are very simple genetic changes, but they cause a cascading effect of alterations to the epigenetic landscape that ultimately become a major driving force behind the cancer. Investigators believe there are many more examples of the genetic/epigenetic collaboration in cancer. Although it is impossible to fix a mutated gene, epigenetic changes can be targeted and disrupted with drugs.
Pediatric oncologist Patrick Brown has found a pattern of genetic/epigenetic collusion in infant leukemia, one of the most treatment-resistant forms of leukemia and one that attacks the youngest of victims. This cancer of blood and bone marrow cells occurs in babies during the first year of life and is set in motion by a rearrangement in a gene called MLL. The gene gets cut and fused to one of about 70 other partner genes.
Dr. Brown has found that all of these partner genes have a common relationship with another gene called DOT1L, an epigenetic gene that modifies DNA packaging in the cell. This morphed fusion gene begins sending epigenetic miscommunications to all of the normal genes in the MLL pathway and causes activation of genes that should be turned off and silences genes that should be turned on. Dr. Brown is beginning a patient study of epigenetic therapy using demethylating and chromatin-modifying drugs to shut down the effects of the fusion gene. Another approach, he says, may be to find a drug that inhibits or deactivates DOT1L, the gene MLL uses to modify the epigenome.
Dr. Yegnasubramanian has uncovered a similar scenario in prostate cancer.
In a study of prostate cancers from men who died of the disease, he found increased methylation in genes not methylated in normal tissue. In each patient studied, this pattern of hypermethylation was consistently maintained across all of the metastatic prostate tumors and occurred near genes in cancer-related pathways that control development and differentiation.
“We need to do more research, but it looks like the areas that have increased methylation are being selected for by the cancer cell to keep its advantage,” says Dr. Yegnasubramanian. “We know these were resistant cancers because we obtained the tumor samples from men who died of prostate cancer. Perhaps if these methylation alterations could have been reversed, the cancer cells might become sensitized to treatments.”
The opportunity to offset the collateral damage to epigenetic functions caused by broken genes is one of the newest and most promising iterations of epigenetic research and one that is rapidly revealing new targets for treatment. Driving this progress is new technology that allows investigators to catalog epigenetic changes and align them back to the genome.
“There are striking differences in how DNA is organized in the cancer cell and how it is organized in the normal cell,” says Dr. Yegnasubramanian. “Now we have the technology to go in and look at this at the molecular level.”
This ability has become critically important with growing evidence that some mutated tumor suppressor genes establish cancers through many subsequent epigenetic alterations. “Although the mutation is the initiating event, it is the epigenetic alterations that are involved in driving the cancer, and unlike mutations, the epigenetic changes can be targeted and halted with drugs,” he said.
Dr. William Nelson
In this era of personalized cancer medicine, many experts believe that epigenetics could be a master control of sorts, so intrinsic to the initiation and spread of cancer that it could potentially provide opportunities to globally reset cancer cells. The panel of epigenetic alterations that drive a particular cancer may vary, but if they can be identified in individual patients, then maybe we have found the Achilles heel of cancer.
Still, most experts agree that science has only scraped the surface when it comes to epigenetics. The understanding of the full power of epigenetic mechanisms to read, write, erase, and move genetic code is just beginning to be understood, but already we have promising treatments.
“If we looked at all of the genes silenced epigenetically in cancer and could turn them all back on, no cancer cell could withstand it,” says Kimmel Cancer Center Director Dr. William Nelson. “We can do that in the laboratory, and now we are learning how to do it safely and effectively in humans. We have tremendous opportunity and unparalleled ingenuity. All we need to do is connect the dots.”