Ethos-PUSH – Studying the Genome and Epigenetic AlterationsJune 30, 2021
Ethos Discovery has made a mission of improving outcomes for dogs with cancer and other complex diseases. As a part of the Ethos-PUSH study for dogs with splenic hemangiosarcoma, we will be gathering tumor samples to study both genetic and epigenetic alterations to provide the most comprehensive look at this highly aggressive disease.
DNA is composed of 4 nucleotides arranged in pairs that are chained together. These nucleotides act as letters and the letters are purposefully ordered so that they can be read out as proteins. For this reason, the genome has been viewed as the language of life. The same letters comprise the dog and all other living organisms’ genomes as well. We all have a genetic blueprint that makes us distinct, yet a paradox has always existed in genetics: Each cell in a multicellular organism shares the same genetic code, but people, animals, plants, and other multicellular organisms are made up of many different types of cells that look and behave differently (i.e. skin cells, immune cells, neurons, kidney cells, etc.). This paradox challenges the notion that DNA sequence alone is what makes us (and our cells) unique.
The word epigenome means “above” the genome and refers to changes on the genome that regulate the expression of genes. If nucleotides are the letters of genetic language, then epigenetic modifications represent the tone of voice, inflection, body language, and context; changes that alter how a spoken or written language is interpreted. In other words, epigenetics is like toppings on a pizza. The pizza itself may be made of the same dough, cheese, and sauce, but toppings will completely change the complexity and flavor of the pizza. Epigenetic modifications are critical for everyday life as they determine which genes are being expressed. It is this concert of gene expression that makes cells unique despite sharing the same genetic code.
Unlike the genetic code, which must be rigorously maintained in the same sequence, the epigenome is more fluid and can change from moment to moment. This allows cells to change gene expression in response to external stimuli. For instance, a cut in our skin triggers a chain reaction that leads to new skin cell formation, invasion of the wound bed, and remodeling of the wound. The cut induces an array of stimuli that triggers the production and then invasion of immune cells, new skin cells, new blood vessels, and more. Once the wound bed is repopulated then the cells must be reorganized to resemble normal skin. Wound healing is a multistep process requiring significant coordination of gene expression in a multitude of cell types. Genetic mutations (alterations to the genetic code) can alter how a cell responds to external stimuli by causing aberrant gene expression. This change in how a cell “should” behave can lead to cancer and other diseases.
The Role of Genetics in Developing New Cancer Treatments
Cancer is a complex disease arising from both genetic and epigenetic alterations. The human genome contains approximately 20,000 genes, and each gene is around 10,000 – 15,000 base pairs long. Yet, the entire human genome is likely around 3 billion base pairs long. This means that much of the human genome is comprised of non-coding regions (not expressed as proteins). This is true for dogs as well. Previously, these non-coding regions were thought of as “trash DNA,” but now it is understood that non-coding regions play a major role in epigenetic regulation of gene expression. For instance, sequences of DNA, called promoters, are present near all genes and are necessary for the binding of proteins that read and transcribe genes. Modifications can be placed on top of the promoter site DNA sequence that block proteins from binding. This results in the gene being “shut off.” Genome-wide epigenetic modifications of promoters and other non-coding regions of the genome are typical of cancer. These epigenetic modifications lead to widespread alterations in gene expression providing the cancer cell with distinct behavior from surrounding normal cells. Newer classes of drugs are being designed to target epigenetic modifications and attempt to restore normal gene expression in cancer cells. The goal of these drugs is to dampen expression of pro-growth genes and force cancer cells to behave more like normal cells. “Epidrugs” have been approved for use against various human cancers but have not yet become a mainstay in veterinary medicine. Through our comprehensive look at hemangiosarcoma, Ethos Discovery will be able to propose novel therapeutic options, including “epidrugs,” that will be vital in curing hemangiosarcoma in dogs. This will also unveil new ways of treating the human equivalent disease, angiosarcoma.