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Blood Cancer Genetic Risk Loci Found in Retriever Dogs

Flat-coated retriever dog

NEW YORK – Genetic alterations in two parts of the dog genome contribute to the risk of a rare immune cell cancer called histiocytic sarcoma that sometimes occurs in flat-coated retrievers, offering clues to related human conditions, according to new research by a team from the National Human Genome Research Institute and elsewhere.

"Strategic breeding can be used to reduce the frequency of the disease over time, and genetic observations may lead to therapeutic options for dogs and humans," Elaine Ostrander, a researcher at NHGRI and the senior and corresponding author of the study, published in PLOS Genetics on Thursday, said in a statement.

Ostrander, NHGRI researcher Jacquelyn Evans, and their colleagues started with a genome-wide association study that included 177 SNP array-genotyped flat-coated retrievers with histiocytic sarcoma and 132 without, narrowing in on loci on chromosome 5 and chromosome 19 that coincided with risk for the aggressive dendritic cell and macrophage cell cancer. They confirmed these results in a validation group that included 94 flat-coated retriever histiocytic sarcoma cases and 43 unaffected controls.

To dig into the apparent risk loci, they turned to whole-genome sequencing, RNA sequencing, and chromatin immunoprecipitation sequencing on samples from several flat-coated retrievers, golden retrievers, or Bernese mountain dogs, another breed with increased histiocytic sarcoma risk.

"Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans," the authors explained. "A histologically and clinically similar counterpart affects flat-coated retrievers at unusually high frequency, with 20 [percent] developing the lethal disease."

The team noted that risk variants at the two canine chromosomal loci flagged in the initial GWAS appeared to collectively explain some 35 to 37 percent of the heritable histiocytic sarcoma risk detected in the disease model dog breed.

"Both regions harbor genes involved in cell migration and cancer-related pathways," the authors wrote, adding that "[i]n identifying genomic differences between affected and unaffected dogs, we advance our understanding of both canine and human health biology, and set the stage for the development of diagnostic and therapeutic strategies."

For their multiomic analysis of the histiocytic sarcoma-linked loci, the researchers sequenced the genomes of five flat-coated retrievers with histiocytic sarcoma and three unaffected control pups from the same breed, analyzing the sequences alongside available genomic data for four golden retrievers with lymphoma. They also incorporated RNA-seq and ChIP-seq data on blood samples from several flat-coated retrievers or Bernese Mountain dogs with or without histiocytic sarcoma to search for informative expression, allele-specific expression, and regulatory shifts in the at-risk dogs.

The data highlighted chromosome 5 variants influencing regulation of the tumor suppressor gene PIK3R6, the team reported. On chromosome 19, meanwhile, the search led to risk variants linked to higher-than-usual expression of TNFAIP6 — a cell migration and metastasis-related gene implicated in human cancer outcomes in prior studies.

"Our study identifies regions of the genome, including two genes with tumor suppressor roles, that increase risk for developing histiocytic sarcoma in flat-coated retrievers," Evans and Ostrander said in an email.

"From these findings, a genetic test could be used to reduce the frequency of the disease over time in this breed," they explained, noting that "the genes and pathways identified herein may provide therapeutic targets for dogs and humans with hematological cancer."