By Carol A Beuchat PhD
Cancer in Dogs
Cancer affects approximately one in three dogs during their lifetime, making it the leading cause of death (Wu et al 2023). The types of cancer encountered are varied, with sarcomas and carcinomas being most common (Rodrigues et al. 2023).
Cancer affects approximately one in three dogs during their lifetime, making it the leading cause of death (Wu et al 2023). The types of cancer encountered are varied, with sarcomas and carcinomas being most common (Rodrigues et al. 2023).
Types of cancer in dogs and commonly affected breeds
Rodrigues L, J Watson, Y Feng, B Lewis, and others. 2023. Shared hotspot mutations in oncogenes position dogs as an unparalleled comparative model for precision thereapeutics. Scientific Reports 13:10935
Rates of cancer in dogs vary widely by breed in purebreds, from about 10% in the Shih Tzu, to as high as 55% Irish Water Spaniel. (Why do dogs get cancer?) The variety in cancer types in dogs and the high rates of incidence across a diversity of breeds make the dog a model animal for translational research.
Cancer mortality in purebred dog breeds
Beuchat CA 2014. Why do dogs get cancer? https://www.instituteofcaninebiology.org/blog/why-do-dogs-get-cancer
Cancer and Body Size
If we look more closely at cancer rates across dog breeds, we find that risk increases with body size. In fact, scientists have argued that this should be expected because larger, longer-lived animals have more cells that undergo many more cell divisions over the lifetime of the animal. If each cell division presents a risk of producing a genetic error that could result in a cancerous cell, larger animals should have more cancer.
If we look more closely at cancer rates across dog breeds, we find that risk increases with body size. In fact, scientists have argued that this should be expected because larger, longer-lived animals have more cells that undergo many more cell divisions over the lifetime of the animal. If each cell division presents a risk of producing a genetic error that could result in a cancerous cell, larger animals should have more cancer.
Rates of cancer in purebred dog breeds over a range in body weight
Beuchat CA. 2015. Do dogs have more ancer than other mammals? https://www.instituteofcaninebiology.org/blog/do-dogs-have-more-cancer-than-other-mammals
Surprisingly, however, if we look not at dogs but at mammals in general, we see something different. Larger species of mammals do not, in fact, have more cancer than small ones. The risk of being afflicted with cancer is about 20% across a diverse array of mammalian species. Even very large and long-lived mammals like elephants do not have higher incidence of cancer than small ones (Abegglen et al 2015; Vincze et al 2022). The single obvious exception is the Tasmanian Devil, which gets one of the rare contagious cancers that is passed from individual to individual when they bite each other, which they apparently do a lot (Stammnitz et al 2023 ).
Cancer rates in mammal species ranging in size from shrew to elephant
Beuchat CA. 2015. Do dogs have more ancer than other mammals? https://www.instituteofcaninebiology.org/blog/do-dogs-have-more-cancer-than-other-mammals
The absence of the expected effect of body size on rates of cancer in mammals is called “Peto's Paradox”. The explanation for the paradox is a topic of lively debate. One popular hypothesis suggests that evolution has resulted in mechanisms to prevent abnormally high rates of cell division that could produce a tumor. This is supported by the discovery that some very large mammals have multiple copies of tumor suppressor genes like TP53, which suppress the growth of tumors by interferring with cell division (Wu et al 2023). Elephants have 20 copies of the TP53 gene, and these multiple copies could crank out more of the proteins that search out and destroy cancer cells (Abegglen et al 2015; Vincze et al 2022).
Now we can see that the increase in cancer risk in larger dogs is an anomaly. Athough there is lots of variability in the data for medium sized dog breeds, most breeds with the highest rates of cancer are larger. The Rottweiler, Leonberger, Bullmastiff, and Golden Retriever have cancer rates higher than 30%, and in some breeds the incidence of cancer exceeds 45%. Notice that large size itself doesn’t doom a breed to develop cancer; the Deerhound and Newfoundland, for example have cancer risk comparable to much smaller breeds, for reasons that remain to be discovered.
Rates of cancer in various species of mammals and in dogs
Beuchat CA. 2015. Do dogs have more ancer than other mammals? https://www.instituteofcaninebiology.org/blog/do-dogs-have-more-cancer-than-other-mammals
Somatic or Germline Mutation?
For me as a comparative biologist, this is all quite fascinating. But for the dogs, it's tragic. There is clearly a puzzle here that we can't explain with our current understanding of cancer in dogs. Since this is just the sort of challenge I like, I began digging around in studies about cancer in dogs. And I discovered something that completely changes how we should think about canine cancer.
We have assumed that cancer in dogs is genetic and that the risk is primarily inherited. This belief has driven a significant amount of research to identify cancer-causing genes so they can be controlled by selective breeding. But while there is evidence of a polygenic associations with cancer risk in some breeds, there are only few examples of single, causative mutations. Of note are mutations in BRCA1 and BRCA2, which are tumor suppressor genes, which increase the risk of mammary cancer in English Springer Spaniels as they do in humans.
Although the search for inherited, cancer-causing mutations in dogs has not been very rewarding, recent research is revealing that we have been looking for the wrong thing.
In fact, researchers are finding that most cancer-causing mutations in dogs are not inherited, i.e., "germ line" mutations but somatic, meaning that they are created during a dog's lifetime.
For me as a comparative biologist, this is all quite fascinating. But for the dogs, it's tragic. There is clearly a puzzle here that we can't explain with our current understanding of cancer in dogs. Since this is just the sort of challenge I like, I began digging around in studies about cancer in dogs. And I discovered something that completely changes how we should think about canine cancer.
We have assumed that cancer in dogs is genetic and that the risk is primarily inherited. This belief has driven a significant amount of research to identify cancer-causing genes so they can be controlled by selective breeding. But while there is evidence of a polygenic associations with cancer risk in some breeds, there are only few examples of single, causative mutations. Of note are mutations in BRCA1 and BRCA2, which are tumor suppressor genes, which increase the risk of mammary cancer in English Springer Spaniels as they do in humans.
Although the search for inherited, cancer-causing mutations in dogs has not been very rewarding, recent research is revealing that we have been looking for the wrong thing.
In fact, researchers are finding that most cancer-causing mutations in dogs are not inherited, i.e., "germ line" mutations but somatic, meaning that they are created during a dog's lifetime.
In a comprehensive study of 2,119 dogs with various types of cancer, researchers found that somatic mutations in TP53, the cancer suppressor gene we talked about earlier, were present in 22.5% of all tumors, making it the most frequently mutated gene across all canine cancers (Rodrigues et al 2023).
Other breed-specific studies have looked at cancer genes across multiple dog breeds and found that, while cancer rates vary dramatically between breeds, which suggests some inherited susceptibility, specific cancer-causing mutations found in tumors were predominantly somatic rather than germline (Alsaihati et al 2021). For example, in osteosarcoma (bone cancer), which affects certain breeds like Golden Retrievers and Rottweilers at much higher rates, 83% of affected dogs had somatic, non-heritable mutations alterations in the TP53 gene (Sakthikumar et al 2018).
Perhaps most convincingly, a massive analysis of 684 canine cancer cases across more than 35 breeds found that the genetic changes driving cancer development were "tumor type-dependent, but largely breed-independent" somatic mutations (Alsaihati et al 2021). This means that while breeds may have different inherited susceptibilities to developing cancer, the actual mutations that cause tumors to grow are largely the same, random, spontaneous events across all breeds.
Other breed-specific studies have looked at cancer genes across multiple dog breeds and found that, while cancer rates vary dramatically between breeds, which suggests some inherited susceptibility, specific cancer-causing mutations found in tumors were predominantly somatic rather than germline (Alsaihati et al 2021). For example, in osteosarcoma (bone cancer), which affects certain breeds like Golden Retrievers and Rottweilers at much higher rates, 83% of affected dogs had somatic, non-heritable mutations alterations in the TP53 gene (Sakthikumar et al 2018).
Perhaps most convincingly, a massive analysis of 684 canine cancer cases across more than 35 breeds found that the genetic changes driving cancer development were "tumor type-dependent, but largely breed-independent" somatic mutations (Alsaihati et al 2021). This means that while breeds may have different inherited susceptibilities to developing cancer, the actual mutations that cause tumors to grow are largely the same, random, spontaneous events across all breeds.
And for breeders that have tried with little success to reduce cancer rates in their breeds, this is a paradigm changer. Because somatic mutations are not present in the germ line, the DNA in every cell, but are created during the lifetime of the dog, they cannot be removed by selective breeding. Put another way, we cannot prevent cancer caused by somatic mutations by trying to select against the mutation itself.
A New Paradigm For Canine Cancer
While breeders can't select directly against somatic cancer-causing mutations, they might be able to select against the genetic backgrounds that increase the susceptibility of genes like TP53 to mutation (Rodrigues et al 2023). But without identifying what these are, a more useful strategy might be to restore genetic diversity that has been lost over generations while cancer incidence has increased. Importantly, restoring diversity might address the risk of many types of cancer in multiple breeds, and make a very real difference in the incidence of cancer in dogs.
While breeders can't select directly against somatic cancer-causing mutations, they might be able to select against the genetic backgrounds that increase the susceptibility of genes like TP53 to mutation (Rodrigues et al 2023). But without identifying what these are, a more useful strategy might be to restore genetic diversity that has been lost over generations while cancer incidence has increased. Importantly, restoring diversity might address the risk of many types of cancer in multiple breeds, and make a very real difference in the incidence of cancer in dogs.
We're at the beginning of a revolution in our understanding of the genetics of cancer in dogs. New discoveries could provide a tremendous opportunity to develop breeding strategies that will reduce canine cancer to the levels seen in other mammals. With a growing toolbox of sophisticated techniques for genetic analysis and the development of resources to design effective breeding strategies to improve genetic variation, we might be on the brink of something extraordinary: a future where most dogs and the people that love them never face cancer at all.
References
Abegglen LM, AF Caulin, A Chan, and others. 2015 Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314:1850-1860. doi:10.1001/jama.2015.13134.
Beuchat, CA 2014. Why do dogs get cancer?
Beuchat, CA 2015. Do dogs have more cancer than other dogs?
Dobson JM 2013 Breed-predispositions to cancer in pedigree dogs. Veterinary Science 2013; doi 10.1155/2013/941275.
Peto R, FJ Roe, PN Lee, L Levy, J Clack. 1975. Cancer and ageing in mice and men. British Journal Cancer 32: 411-426.
Rivera P, M Melin, T Biagi, T Fall, J Haggstrom, K Lindblad-Toh, H von Euler. 2009. Mammary tumor development in dogs is associated with BRCA1 and BRCA2. Cancer Research 69: 8770-8774. doi: 10.1158/0008-5472.CAN-09-1725.
Rodrigues L, J Watson, Y Feng, B Lewis, et al. 2023. Shared hotspot mutations in oncogenes position dogs as an unpaalleled comparative model for precision therapeutics. Scientific Reports 13:10935. doi.org/10.1038/s41598-023-37505-2.
Sakthikumara S, M Warrier, D Whitley, S Facista, J Adkins, et al 2018. Genomic analysis across 53 canine cancer types reveals novel mutataions and high clinical actionability potential. Veterinary Comparative Oncology 22: 30-41. DOI: 10.1111/vco.12944.
Stammnitz et al 2023. The evolution of two transmissible cancers in Tasmanian devils. Science 380: 283-293. DOI: 10.1126/science.abq6453.
Sulak M, L Fong, K Mika, et al. MS. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife 5:e11994. doi: 10.7554/eLife.11994.
Vincze O et al. 2022 Cancer risk across mammals. Nature 60:263267. doi:10.1038/ s41586-021-04224-5.
Abegglen LM, AF Caulin, A Chan, and others. 2015 Potential mechanisms for cancer resistance in elephants and comparative cellular response to DNA damage in humans. JAMA 314:1850-1860. doi:10.1001/jama.2015.13134.
Beuchat, CA 2014. Why do dogs get cancer?
Beuchat, CA 2015. Do dogs have more cancer than other dogs?
Dobson JM 2013 Breed-predispositions to cancer in pedigree dogs. Veterinary Science 2013; doi 10.1155/2013/941275.
Peto R, FJ Roe, PN Lee, L Levy, J Clack. 1975. Cancer and ageing in mice and men. British Journal Cancer 32: 411-426.
Rivera P, M Melin, T Biagi, T Fall, J Haggstrom, K Lindblad-Toh, H von Euler. 2009. Mammary tumor development in dogs is associated with BRCA1 and BRCA2. Cancer Research 69: 8770-8774. doi: 10.1158/0008-5472.CAN-09-1725.
Rodrigues L, J Watson, Y Feng, B Lewis, et al. 2023. Shared hotspot mutations in oncogenes position dogs as an unpaalleled comparative model for precision therapeutics. Scientific Reports 13:10935. doi.org/10.1038/s41598-023-37505-2.
Sakthikumara S, M Warrier, D Whitley, S Facista, J Adkins, et al 2018. Genomic analysis across 53 canine cancer types reveals novel mutataions and high clinical actionability potential. Veterinary Comparative Oncology 22: 30-41. DOI: 10.1111/vco.12944.
Stammnitz et al 2023. The evolution of two transmissible cancers in Tasmanian devils. Science 380: 283-293. DOI: 10.1126/science.abq6453.
Sulak M, L Fong, K Mika, et al. MS. TP53 copy number expansion is associated with the evolution of increased body size and an enhanced DNA damage response in elephants. Elife 5:e11994. doi: 10.7554/eLife.11994.
Vincze O et al. 2022 Cancer risk across mammals. Nature 60:263267. doi:10.1038/ s41586-021-04224-5.
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