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• W2022700957 abstract "Thousands of years after our human ancestors began domesticating dogs, selective mating has yielded more than 350 breeds as distinctive as Great Danes and Chihuahuas within the past few centuries. The reduced genetic diversity within breeds has greatly increased the risk for a wide range of cancers and other diseases. Golden retrievers, for example, are particularly susceptible to lymphomas and hemangiosarcomas. Bernese mountain dogs, Rottweilers, and flat-coated retrievers are at higher risk for histiocytic neoplasms; and Scottish terriers frequently develop bladder cancer. Roughly 1 in 4 of the 83 million dogs in the United States, in fact, will be diagnosed with cancer at some point in their lifetime. Scientists, however, are discovering a critical silver lining that may aid both us and our beloved canine companions. Because much of the genetic heterogeneity has been removed from purebreds, researchers can more easily identify the genetic signatures of increased cancer risk within dog genomes. Those genetic factors, in turn, may help scientists identify the mechanisms of action and pinpoint potential therapeutic targets in dogs and humans alike. “Cancer research is now bidirectional,” said Matthew Breen, PhD, professor of genomics at the North Carolina State University College of Veterinary Medicine in Raleigh, during a recent presentation to journalists at the Council for the Advancement of Science Writing conference in Gainesville, Florida. “We take information from people and translate it to dogs, and take information from dogs and translate it to people.” If researchers looked solely within the human genome to understand the genetic basis of a specific cancer, Dr. Breen says, they would struggle to separate the driver mutations from the passengers that are merely along for the ride. But many cancers share highly conserved features across multiple species. By studying a pathologically comparable form of cancer, researchers can identify the cancer-linked genes shared across species. In many human patients with meningioma, scientists have detected a deletion of the long arm of chromosome 22 (22q), which includes about 50 million base pairs and more than 500 genes. In half of all canine meningiomas, by contrast, Dr. Breen and colleagues have implicated a complete loss of chromosome 27. The respective deletions in the dog and human genomes only overlap by about 2 million bases, suggesting that the lost human genes correspond to a relatively small piece of dog chromosome 27. The researchers are preparing to examine the role of those genes in a panel of 200 tumor samples from human meningioma patients. Kerstin Lindblad-Toh, PhD, professor of comparative genomics at Uppsala University in Sweden and scientific director of vertebrate genome biology at the Broad Institute in Cambridge, Massachusetts, led the collaborative effort that yielded the sequenced dog genome in 2005. With the genome in hand, she says, researchers believed the inherent structure of dog breeds would lend itself particularly well to mapping disease-linked genes. “I think what's in some ways surprising is that it's really true,” Dr. Lindblad-Toh says. “It's much easier to find the disease genes in dogs than in humans, and that's really exciting.” As another case in point, she cited a recent collaboration with Dr. Breen and others that used genome-wide association analyses in greyhounds, Rottweilers, and Irish wolfhounds to link 33 genomic regions to an increased risk of osteosarcoma.1 Clinical progression of osteosarcoma is nearly identical in dogs and humans. The study, Dr. Lindblad-Toh says, shows that a rare disease in humans can be relatively common in specific dog breeds, and that relatively few dogs—blood samples from less than 600 were included in the final dataset—are required to tease out relevant factors. Although the effort uncovered slightly different risk factors within each breed, the implicated pathways connected back to bone growth and differentiation, suggesting that multiple drivers of the disease may converge upon the same functional mechanism. Jaime Modiano, VMD, PhD, Perlman professor of oncology and comparative medicine and director of the Animal Cancer Care and Research Program at the University of Minnesota in Minneapolis, collaborated with Drs. Lindblad-Toh and Breen on the osteosarcoma study. Dr. Modiano and a team of researchers are now hoping to take a more holistic view of the cancer. Among their questions: What do populations of osteosarcoma-susceptible dogs, mice, and humans have in common? Do traits shared across species similarly influence disease progression, metastasis, and treatment response? Why do dogs get the cancer when they're old while people tend to get it when they're young? “It's been really gratifying that the information we've been able to find in dogs has completely unmasked information that was there in people but we were unable to find it because of the vast level of heterogeneity at the genetic level of human individuals,” Dr. Modiano says. He and his colleagues, in conjunction with a commercial partner, are now developing and validating 2 linked tests that rely on just 2 genes and a few microRNA sequences to predict how osteosarcoma might respond to treatment. Eventually, he says, the tests may give clinicians important new insights about how aggressively a child's tumor should be treated. The 3 laboratories and other groups are also jointly developing a genetic assay that can identify golden retrievers at high risk for lymphoma and hemangiosarcoma. Roughly one-third of all golden retrievers die from one of these 2 cancers, Dr. Breen says. The assay, soon to be commercialized, is based on specific genomic sequences that can accurately separate the dogs into high-risk and low-risk groups. The eventual value of this information, however, could extend far beyond a single breed. The collaborators have since launched a follow-up project that analyzes whether the same genetic factors are detectable in other breeds. If so, a genetic signature for lymphoma and hemangiosarcoma across dog breeds could be used as bait to fish for something similar in humans. Although Dr. Breen doubts whether physicians will ever be able to completely cure all cancers, he says earlier diagnoses and interventions could transform many into a more manageable chronic disease, like diabetes. Getting from here to there will require a far more thorough understanding of the underlying genetic mechanisms, but the key to unlocking much of that information, he says, “may have been walking right beside us for many, many years.” Growing evidence that dogs can pick up the faint but distinctive scent of human tumors is driving a unique research effort that could yield a sort of electronic nose for the early detection of ovarian cancer. Many human diseases leave telltale traces through specific odors, and multiple studies have suggested that dogs, which boast a sense of smell 10,000 to 100,000 times as acute as our own, may be able to sniff out melanoma, prostate, lung, and other cancers.2 George Preti, PhD, an organic chemist at the Monell Chemical Senses Center at the University of Pennsylvania in Philadelphia, and colleagues are hoping to take the next step. Their ultimate goal: a dog-inspired, odor-tracking device that could be used by a clinician or health professional to do routine cancer screening on blood, saliva, or other body fluids. “This is a very nontraditional look at cancer diagnosis,” Dr. Preti says, noting that most screening techniques are based on visual scans. “People have not focused on odor information, which is just as rich and just as varied.” Through a collaboration with cancer clinicians, a physicist, and the University of Pennsylvania's Working Dog Center, he hopes to show that ovarian cancer can be detected through a specific signature of volatile organic compounds. If so, a sensor could be tuned to that specific chemical combination. First, several canine assistants are being trained to detect the signature smell in serum from ovarian cancer patients. “Next, we have to identify what the odorants are that make up the odor signature,” Dr. Preti says. He can use gas chromatography to separate out various components of the complex mixture. Here again, trained dogs may help him pinpoint which ones contain the causative odor. “The dog is like a bioassay,” he says." @default.
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• W2022700957 date "2014-05-01" @default.
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• W2022700957 title "In dogged pursuit of cancer's genetic origins: Researchers are using the increased cancer susceptibility within specific dog breeds to benefit both canines and humans" @default.
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• W2022700957 doi "https://doi.org/10.1002/cncy.21438" @default.
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