Genetic analysis of several hundred dogs revealed that breeds predisposed to histiocytic sarcoma have corresponding gene variants, and because humans are also susceptible to this rare form of cancer, the findings could help inform therapeutic strategies for canines and people alike.
The genome-wide association study was published April 1 in PLOS Genetics. It identified four new markers of histiocytic sarcoma in dogs prone to developing the cancer and confirmed that previously known genetic components of the illness were correct.
"Up to 20% of Bernese mountain dogs are dying from this cancer," said Benoît Hédan, lead author of the study and a postdoctoral researcher at the Institute of Genetics and Development of Rennes. "Since there are not efficient treatments in dogs, it is estimated that dogs die from HS in an average 45 days after the diagnosis."
Histiocytic sarcoma, or HS, manifests in certain dog breeds, particularly Rottweilers, golden retrievers, flat-coated retrievers and Bernese mountain dogs. This selection is mainly due to selective breeding methods that directly manipulate the dogs' genome. That includes inbreeding, also referred to as consanguinity.
"The dog — with over 400 breeds and a unique diversity of phenotypes — shows predisposition to numerous diseases," Hédan said. "It results from the breed creation, breeder selections and consanguinity."
This cancer begins in tissues of the hematopoietic system, such as bone marrow. It's very aggressive and fatal in humans as well, and can also lead to the development of other cancers, such as lymphoma.
However, because histiocytic sarcoma is so uncommon in humans, it's tremendously difficult to discover any diagnostic tools or treatment strategies for it, especially using broad meta-analysis studies, Hédan told The Academic Times.
"Human HS is extremely rare, and it is unknown if there are predisposing factors in humans for this cancer," he said. "With only four to five cases per year in France, these studies are almost impossible in humans."
"Nevertheless," Hédan continued, "understanding what genes … lead to this cancer in dogs will help to prevent or treat this cancer in humans."
Subject limitations are less relevant for dogs because — again, due to selective breeding methods — they have much more standardized genes. The research team was able to conduct a reasonably in-depth genetic analysis with a total of 453 affected dogs and 385 healthy controls.
"This is an advantage of the dog model," Hédan explained. "With a more homogenous population, it is easier to identify [a] predisposing region with a smaller number of cases and controls."
The new study draws from Hédan's work published in 2020, which solidified the first gene crossovers between dogs and humans with histiocytic sarcoma. He said the team's dog model also prompted the development of the first and only test for cancer predisposition in dogs, and specifically in Bernese mountain dogs, allowing researchers to sequence their DNA.
Genome-wide association studies explore genome sequences of individual participants. In this case, veterinarians provided the canine subjects' DNA. Researchers then look at the individual gene variants, or alleles, of each participant and seek to identify consistently atypical sections. Those sections are then compared to an expressed trait, called a phenotype.
In Hédan's study, the atypical sections were collections of "subregions" in the genome, rather than specific genes. That means the team found that various risk alleles were combined in dogs predisposed to histiocytic sarcoma.
"We identified numerous 'subregions' involved in the predisposition," he said. "We were expecting that a predisposing region is due to a specific mutation, but in fact, it seems that it is resulting from the accumulation of numerous mutations across the subregions."
That means that in humans, too, this cancer is likely due to the collection of such alleles that seemingly lead to its expression. In the future, Hédan hopes to be able to refine the dog model for histiocytic sarcoma even further.
Typically, meta-analysis and genome-wide association studies must be conducted more than once to validate results. This concept is so vital that data scientists are trying to find ways to mitigate the burden of redoing such time-consuming studies.
"We hope that dogs could help to develop new, efficient therapies for humans — but also for dogs," Hédan said. The team believes that in addition to humans, affected dogs should benefit from clinical trials and genetic analyses like this one.
The paper, "Identification of common predisposing loci to hematopoietic cancers in four dog breeds," published April 1 in PLOS Genetics, was authored by Benoît Hédan, Edouard Cadieu, Maud Rimbault, Amaury Vaysse, Pascale Quignon, Thomas Derrien, Catherine André and Nadine Botherel, IGDR; Caroline Dufaure de Citres, Antagene; and Patrick Devauchelle, Micen Vet and Jérôme Abadie, LabOniris.