TGen-led canine melanoma study identifies genetic basis of disease; potential drug targets
PHOENIX, Ariz. — Sept. 6, 2018 — As a veterinarian, Dr. Carolyn Duregger is familiar with the telltale signs of canine melanoma. So when she gave her own dog, Parker, a routine oral examination, the 1-centimeter-diameter discolored lump in the pup's upper right gums took her breath away.
"It's an aggressive cancer with poor prognosis that I've seen many times. My stomach dropped. I literally gasped," said Dr. Duregger, recalling the moment she realized her fluffy, 9-year-old Wheaten terrier might be in big trouble.
Dr. Duregger surgically removed the cancerous lump, and started Parker on radiation and an immunotherapy drug. But these measures don't always last, which is why she whole-heartedly supports the molecular-level precision medicine research led by the Translational Genomics Research Institute (TGen), an affiliate of City of Hope.
In the most comprehensive study of its kind, TGen and its collaborators from across the nation used multiple genomic analysis techniques to identify several gene mutations that could be the keys to what drives melanoma in dogs. Following the path from human melanoma, the findings of recurring molecular changes in canine melanoma can help veterinary physicians pinpoint potential new treatments for dogs. Likewise, human physicians will view these changes in light of the type of melanoma that occurs in non-sun exposed areas (as in the case of Parker) in the mouth, or other mucosal surfaces.
Researchers specifically identified mutations in a gene called PTPRJ, a tumor suppressor gene, according to the multi-year study published today in the journal PLOS Genetics.
"This mutational landscape of canine melanoma resembles that seen in human melanoma subtypes found in sun-shaded areas of the body, such as the nose and mouth, which remain difficult to treat. This similarity means that we have a genetic bridge across which understanding of the disease in either species can inform the other," said Dr. Will Hendricks, a TGen Assistant Professor of Integrated Cancer Genomics, and the study's lead author.
While melanoma is commonly associated with skin cancer, different types of melanoma can originate in different parts of the body, and it often spreads to the lungs, lymph nodes, bones and brain.
Researchers looked at 37 canine tumors and 17 control samples from a variety of dog breeds, and used several genomic analysis tools, including: whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses.
"Malignant melanoma is a significant cause of death among domestic dogs, and also provides a powerful comparative model for melanoma among humans," said Dr. Jeffrey Trent, TGen President and Research Director, and the study's senior author. "Overall, these data inform biological comparisons between canine and human melanoma, while suggesting actionable targets for both."
The study found mutations in the PTPRJ tumor suppressor gene in seven of the tumors, and cancer-activating mutations in the RAS gene in nine of the tumors, in addition to changes in the genes MDM2 and TP53.
"Our genetic understanding of canine melanoma now allows us to continue to work to understand melanoma biology, and serves as a roadmap to developing and evaluating new treatment strategies," Dr. Hendricks said.
The study examined several dog breeds with a propensity for melanoma, including Cocker Spaniels, an English Cocker Spaniel and a Labrador retriever. The paper — Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine malignant melanoma by integrated comparative genomic analysis — notes that an expanded study of breed-specific groups will be critical for further understanding of melanoma among dogs.
Also contributing to this study were: the National Cancer Institute (NCI); Mayo Clinic; Arizona State University; North Carolina State University; University of California, Davis; Colorado State University; University of Queensland; Van Andel Research Institute; Spectrum Health; Innogenics Inc.; and The Veterinary Cancer Center.
Funding for this study was provided by: the National Institutes of Health (NIH), award numbers UM1 CA186689 and UC2 CA148149; the National Cancer Institute (NCI), award number P30CA016058; Stand Up To Cancer (SU2C), award number SU2C-AACR-DT0612; Brooke's Blossoming Hope for Childhood Cancer Foundation; the North Carolina State University (NCSU) Cancer Genomics Fund; Dell Inc.; and the TGen Foundation.
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based non-profit organization dedicated to conducting groundbreaking research with life changing results. TGen is affiliated with City of Hope, a world-renowned independent research and cancer and diabetes treatment center: http://www.cityofhope.org. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes, and infectious diseases, through cutting edge translational research (the process of rapidly moving research towards patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and rare complex diseases in adults and children. Working with collaborators in the scientific and medical communities literally worldwide, TGen makes a substantial contribution to help our patients through efficiency and effectiveness of the translational process. For more information, visit: http://www.tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.
TGen Senior Science Writer
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