Kate Megquier, DVM
When people hear that I am a veterinarian, they are often surprised to learn that I work in a genetics lab, rather than in the clinic with a white coat and a stethoscope. I began studying the genomic basis of cancers in dogs when I was in veterinary school because I wanted to help further translational research – that is, I wanted to help make discoveries that could be translated into new clinical treatments and diagnostics for pets. Along the way, I have come to understand that this research is also important from a comparative medicine perspective: understanding cancer in dogs can also teach us about cancer in people. It’s a win-win scenario!
In this post, I’d like to give you a brief overview of how our lab studies cancer in dogs, and hint at a few exciting new studies that we will be starting in the near future!
Inherited risk factors
One way that we study cancers in dogs is by looking for genetic risk factors that predispose them to developing cancer. Genetic risk factors for cancer tend to run in highly related dog breeds, meaning that these risk factors are passed down (inherited) from generation to generation. This is somewhat similar to how cancers can run in human families – for example, you may have heard about how individuals in families with an inherited mutation in a BRCA gene often have an elevated risk of breast, ovarian, or prostate cancer.
When we look for inherited risk factors, we search the entire genome for regions that contain mutations with different frequencies in dogs with and without cancer. This is called a genome-wide association study. These regions harbor genetic variants that affect the risk of developing cancer. We work with collaborators to understand the inherited risk factors behind multiple cancer types. Interestingly, risk factors for a given cancer sometimes differ across breeds who all get the same cancer type. For example, we’ve shown that three breeds predisposed to osteosarcoma have different genetic risk factors, but these risk factors impact genes that work together. Studying whether carrying these risk factors can predict the development of disease or how the disease will act clinically will aid in developing new diagnostic tests. In addition, we are continuing to investigate what these genetic changes are doing at the cellular level that is leading to cancer. Knowing this will help to better understand the underlying disease and potentially to develop new therapies in the future.
It is now well-known that exposure to certain agents called carcinogens (think tobacco smoke, asbestos, or radiation, to name only a few) can increase the risk of developing cancer. Because our dogs live in the same environment as we do, studying how these agents affect the risk of cancer in our dogs not only helps us to keep them safe, but can also help to identify agents that may be harmful to humans. Tobacco smoke is one example of a shared environmental exposure leading to cancer. One of the best-known risk factors in human respiratory tract cancers, it has been shown to increase the risk of nasal and sinus cancer as well as lung cancer in dogs. Because many dogs live their entire lives with the same owner in the same house, their exposure to certain types of carcinogens can be tracked, either with owner questionnaires or with publicly available information on pollution levels and other risk factors in the area that they live. In addition, recent research has shown that silicone rubber (you know, those LIVESTRONG bracelets?) can be used as a passive sampler to track exposure to various compounds. We are excited to be planning a pilot study looking at whether silicone collar tags can be used to track environmental exposure levels of various compounds in dogs, so stay tuned for that!
In addition to inherited mutations, we are also interested in mutations that occur during the lifetime of a cell, called somatic mutations. These can arise from either genetic (for example, faulty DNA repair genes) or environmental (carcinogen exposure) causes. This type of mutation is what is being referred to when doctors perform sequencing of a tumor.
Somatic mutations are important in understanding the behavior of a tumor clinically. Two important types of gene that are frequently mutated in cancers are oncogenes and tumor suppressors, and these are often described using the analogy of the cell as a car. Oncogenes are like the gas pedal – the tumor wants to go fast, meaning that it wants to proliferate and divide. A mutation in an oncogene causes the gas pedal to be stuck down, and cells proliferate out of control. Tumor suppressors, on the other hand, are like the brakes in this analogy – these are genes that can stop uncontrolled cell division and induce apoptosis (cell death). Many cancers disable the brakes through mutation or deletion of these tumor suppressor genes.
Traditionally, cancer has been treated in three ways: surgical removal of the tumor, irradiation of the tumor site, and chemotherapy, which targets all fast-dividing cells. But cancer cells aren’t the only ones in the body that divide fast. This is also true for hair, immune cells and the cells lining the gut. The fact that the chemotherapy also harms these cell types leads to side effects such as increased risk of infection, nausea, and sometimes hair loss. Recently, however, new drugs called “targeted therapies” have begun to be designed. These drugs can target cancer cells with a particular mutation, and spare the normal tissue. Going back to our car analogy, it’s as if knowing how the cancer disabled the brakes allows us to selectively re-engage them, rather than having to target all fast-moving cars.
This is one of the goals of precision medicine – to be able to sequence a patient’s tumor and select a targeted therapy specifically designed for the mutations in that tumor, without causing damage to the normal tissue. There are a number of targeted therapies already in use in human medicine, for example, the drug vemurafenib targets a mutation in a gene called BRAF in patients with melanoma. A few have been approved for use in veterinary medicine, for example, toceranib is used to treat dogs with mast cell tumors. The more we know about the underlying mutations in different types of cancer, the better we can design targeted therapies for these mutations and help to treat more patients. Dogs will be important in this effort both for veterinary medicine and for human medicine, as many cancers that are rare in people are actually common and more easily studied in dogs.
In order to sequence somatic mutations, we need to be able to sample the tumor’s DNA. Usually, this means that a tumor biopsy must be performed, and DNA prepared directly from a portion of tumor tissue. Recent advances in sequencing techniques are allowing researchers to sequence the tumor from fragments of DNA floating in the bloodstream, rather than having to physically sample the tumor itself so that the patient doesn’t need to undergo surgery. This technique, called “liquid biopsy,” opens up many possibilities, including improved diagnostic tests, repeated sampling of tumor DNA over the course of therapy to monitor response and development of chemotherapy resistance, and monitoring patients in remission for signs of relapse. We are very excited to be piloting the use of this technique to sequence tumor DNA in dogs, with the help of the Adalsteinsson lab, who are pioneering this technique at the Broad Institute. Stay tuned for more information on this pilot study as it unfolds!
This has been a bit of a whirlwind tour of some the things we look at now and are planning to look at in our canine cancer studies. I hope to write in more detail about some of these topics in the future as we embark on our new studies and publish new findings.